Primary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

ABSTRACT

The present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A  serotonin receptor. 
     
       
         
         
             
             
         
       
     
     Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette&#39;s syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. 
     The present invention also relates to the methods for the treatment of 5-HT 2A  serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.

FIELD OF THE INVENTION

The present invention pertains to certain compounds of Formula (Ia) andpharmaceutical compositions thereof that modulate the activity of the5-HT_(2A) serotonin receptor. Compounds and pharmaceutical compositionsthereof are directed to methods useful in the treatment of plateletaggregation, coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, atrial fibrillation, blood clotformation, asthma or symptoms thereof, agitation or a symptom thereof,behavioral disorders, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorder, psychosis, acute schizophrenia, chronicschizophrenia, NOS schizophrenia and related disorders, sleep disorders,diabetic-related disorders, progressive multifocal leukoencephalopathyand the like.

The present invention also relates to the methods for the treatment of5-HT_(2A) serotonin receptor associated disorders in combination withother pharmaceutical agents administered separately or together.

BACKGROUND OF THE INVENTION

G Protein Coupled Receptors

G Protein coupled receptors share a common structural motif. All thesereceptors have seven sequences of between 22 to 24 hydrophobic aminoacids that form seven alpha helices, each of which spans the membrane.The transmembrane helices are joined by strands of amino acids having alarger loop between the fourth and fifth transmembrane helix on theextracellular side of the membrane. Another larger loop, composedprimarily of hydrophilic amino acids, joins transmembrane helices fiveand six on the intracellular side of the membrane. The carboxy terminusof the receptor lies intracellularly with the amino terminus in theextracellular space. It is thought that the loop joining helices fiveand six, as well as, the carboxy terminus, interact with the G protein.Currently, Gq, Gs, Gi and Go are G proteins that have been identified.

Under physiological conditions, G protein coupled receptors exist in thecell membrane in equilibrium between two different states orconformations: an “inactive” state and an “active” state. A receptor inan inactive state is unable to link to the intracellular transductionpathway to produce a biological response. Changing the receptorconformation to the active state allows linkage to the transductionpathway and produces a biological response.

A receptor may be stabilized in an active state by an endogenous ligandor an exogenous agonist ligand. Recent discoveries such as, includingbut not exclusively limited to, modifications to the amino acid sequenceof the receptor provide means other than ligands to stabilize the activestate conformation. These means effectively stabilize the receptor in anactive state by simulating the effect of a ligand binding to thereceptor. Stabilization by such ligand-independent means is termed“constitutive receptor activation.”

Serotonin Receptors

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an importantclass of G protein coupled receptors. Serotonin is thought to play arole in processes related to learning and memory, sleep,thermoregulation, mood, motor activity, pain, sexual and aggressivebehaviors, appetite, neurodegenerative regulation, and biologicalrhythms. Not surprisingly, serotonin is linked to pathophysiologicalconditions such as anxiety, depression, obsessive compulsive disorders,schizophrenia, suicide, autism, migraine, emesis, alcoholism, andneurodegenerative disorders. With respect to anti-psychotic treatmentapproaches focused on the serotonin receptors, these types oftherapeutics can generally be divided into two classes, the “typical”and the “atypical.” Both have anti-psychotic effects, but the typicalsalso include concomitant motor-related side effects (extra pyramidalsyndromes, e.g., lip-smacking, tongue darting, locomotor movement, etc).Such side effects are thought to be associated with the compoundsinteracting with other receptors, such as the human dopamine D₂ receptorin the nigro-striatal pathway. Therefore, an atypical treatment ispreferred. Haloperidol is considered a typical anti-psychotic, andclozapine is considered an atypical anti-psychotic.

Serotonin receptors are divided into seven subfamilies, referred to as5-HT₁ through 5-HT₇, inclusive. These subfamilies are further dividedinto subtypes. For example, the 5-HT₂ subfamily is divided into threereceptor subtypes: 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C). The human5-HT_(2C) receptor was first isolated and cloned in 1987, and the human5-HT_(2A) receptor was first isolated and cloned in 1990. These tworeceptors are thought to be the site of action of hallucinogenic drugs.Additionally, antagonists to the 5-HT_(2A) and 5-HT_(2C) receptors arebelieved to be useful in treating depression, anxiety, psychosis, andeating disorders.

U.S. Pat. No. 4,985,352 describes the isolation, characterization, andexpression of a functional cDNA clone encoding the entire human5-HT_(1C) receptor (now known as the 5-HT_(2C) receptor). U.S. Pat. Nos.5,661,024 and 6,541,209 describe the isolation, characterization, andexpression of a functional cDNA clone encoding the entire human5-HT_(2A) receptor.

Mutations of the endogenous forms of the rat 5-HT_(2A) and rat 5-HT_(2C)receptors have been reported to lead to constitutive activation of thesereceptors (5-HT_(2A): Casey, C. et al. (1996) Society for NeuroscienceAbstracts, 22:699.10, hereinafter “Casey”; 5-HT_(2C): Herrick-Davis, K.,and Teitler, M. (1996) Society for Neuroscience Abstracts, 22:699.18,hereinafter “Herrick-Davis 1”; and Herrick-Davis, K. et al. (1997) J.Neurochemistry 69(3): 1138, hereinafter “Herrick-Davis-2”). Caseydescribes a mutation of the cysteine residue at position 322 of the rat5-HT_(2A) receptor to lysine (C322K), glutamine (C322Q), and arginine(C322R) which reportedly led to constitutive activation. Herrick-Davis 1and Herrick-Davis 2 describe mutations of the serine residue at position312 of the rat 5-HT_(2C) receptor to phenylalanine (S312F) and lysine(S312K), which reportedly led to constitutive activation.

SUMMARY OF THE INVENTION

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;

wherein:

X is O or S;

V is O or NH;

W is C₁₋₄ alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₁₋₃ haloalkyl,halogen, oxo and imino, wherein the C₁₋₃ alkyl is optionally substitutedwith C₁₋₃ alkylsulfonyl;

Z is C₁₋₄ alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; orZ is absent;

R¹ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₃₋₇ cycloalkyl;

R² is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol, nitro andsulfonamide;

R³ is selected from the group consisting of H, C₂₋₆ alkenyl, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofthe C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;

R^(4a) is H;

R^(4b) is H, or a mono-valent-metabolically-labile group; or

R^(4a) and R^(4b) together with the nitrogen to which they are bothbonded form a divalent-metabolically-labile group;

R⁵, R⁶ and R⁷ are each selected independently from the group consistingof H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro;

and

R⁸ is C₁₋₈-alkyl, aryl, C₃₋₁₀ cycloalkyl, heteroaryl, or heterocyclyleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₆ alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₈ dialkylcarboxamide, C₂₋₈dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio,heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl,wherein the C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,C₁₋₆ alkylimino, C₂₋₈ dialkylamino, heteroaryl, heterocyclyl, phenyl,and phenoxy, and each the substituent is optionally substituted with 1,2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋6 alkylamino, C₂₋₈ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylcarboxamide,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclyl, hydroxyl, thiol andnitro.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a compound of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for modulatingthe activity of a 5-HT_(2A) serotonin receptor by contacting thereceptor with a compound according to any of the embodiments describedherein or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) associated disorder in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) serotonin receptor associated disorder in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein wherein R^(4b) is amono-valent-metabolically-labile group.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) serotonin receptor associated disorder in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a prodrug whereby the prodrugundergoes a conversion into a compound according to any of theembodiments described herein wherein R^(4a) and R^(4b) are both H andthe conversion takes place within the body of the individual.

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a compound according to any of theembodiments described herein and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to the use of a compound ofthe present invention for the production of a medicament for use in thetreatment of a 5-HT_(2A) associated disorder.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method of treatmentof the human or animal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of a 5-HT_(2A) associated disorder, as described herein, inthe human or animal body by therapy.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 1 shows a generalcoupling method between a pyrazole boronic acid and an aryl triflate, itis understood that similar coupling methods known in the art can also beused, and a halide, such as, I, Br or Cl, can be used in place of thetriflate.

FIG. 2 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention wherein “V” is oxygen.FIG. 2 shows a general coupling method between a pyrazole boronic acidand a phenyl halide using coupling methods known in the art, such as aSuzuki coupling, and the like. FIG. 2 further shows the use oforthogonal protecting groups for the oxygen (V=O) and the nitrogen.After the coupling reaction, the phenol protecting group is removed anda variety of —W—NR^(4a)R^(4b) groups can be introduced. Subsequently,the alkyl amide protecting group can be hydrolyzed to provide the amineintermediate of the present invention.

FIG. 3 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 3 illustratesgeneral methods for introducing a variety of halogens to compounds ofthe invention. It is understood that these halogenation reactions canalso be conducted later in the synthesis, for example as the last step.

FIG. 4 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 4 shows thegeneral reactions, such as, alkylation and Mitsunobu-like reactions, forintroducing the —W—NR^(4a)R^(4b) group.

FIG. 5 shows the general synthetic scheme for the preparation ofcompounds of the present invention. FIG. 5 shows the general couplingreactions of the amino-intermediate with carboxylic acids, acyl halides,and the like.

FIG. 6 shows the general synthetic scheme for the preparation ofintermediates and compounds of the present invention. FIG. 6 illustratesthe general methods for preparing pyrazoles of the present inventionusing substituted and unsubstituted hydrazines.

FIG. 7 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein the —W—NR^(4a)R^(4b) group isintroduced in the last step(s). FIG. 7 shows the general reactions, suchas, alkylation and Mitsunobu-like reactions, for introducing the—W—NR^(4a)R^(4b) group.

FIG. 8 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein V is NH in Formula (Ia) and the—W—NR^(4a)R^(4b) group is introduced in the last step(s). FIG. 8 showsthe general reactions, such as, alkylation reactions, for introducingthe —W—NR^(4a)R^(4b) group wherein V is NH.

DEFINITIONS

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonists” shall mean moieties that interact and activate thereceptor, such as the 5-HT_(2A) receptor, and initiates a physiologicalor pharmacological response characteristic of that receptor. Forexample, when moieties activate the intracellular response upon bindingto the receptor, or enhance GTP binding to membranes.

The term “antagonist” is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

The term “contact or contacting” is intended to mean bringing theindicated moieties together, whether in an in vitro system or an in vivosystem. Thus, “contacting” a 5HT_(2A) receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual, preferably a human, having a 5HT_(2A)receptor, as well as, for example, introducing a compound of theinvention into a sample containing a cellular or more purifiedpreparation containing a 5HT_(2A) receptor.

The term “mono-valent-metabolically-labile group” as used herein refersto any group that, following administration of a compound containing thegroup to an individual, is converted in vivo to a compound of Formula(Ia) wherein R^(4b) is H. The conversion of the “firstmetabolically-liable group” can be by metabolic and/or chemicalprocesses and can occur in one step or through a series of two or moresteps. Representative examples of a “mono-valent-metabolically-labilegroup” include, but are not limited to, —C(═O)O—R^(4c) (thus, togetherwith the nitrogen forms a carbamate), —C(═O)—R^(4c) (together with thenitrogen forms an amide), and the like, wherein R^(4c) is C₁₋₁₈ alkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl each optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl, and sulfonamide. Insome embodiments, the “mono-valent-metabolically-labile group” is C₁₋₁₂acyl, carbo-C₁₋₆-alkoxy, or C(═O)O-aryl, wherein the C₁₋₁₂ acyl,carbo-C₁₋₆-alkoxy, and —C(═O)O-aryl are each optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₆ alkylcarboxamide, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, C₁₋₆ alkylimino, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, halogen, nitro, and phenyl; or R^(4b) is—C(═O)OCR^(a)R^(b)OC(═O)R^(c), wherein R^(a), R^(b) and R^(c) are eachindependently selected from H, or C₁₋₆ alkyl. The groups illustrated areexemplary, not exhaustive, and one skilled in the art could prepareother known varieties of groups. In some cases, a“mono-valent-metabolically-labile group” (i.e., R^(4b)) can serve toimprove efficacy or safety through improved oral bioavailability, orpharmacodynamic half-life, etc.

The term “in need of treatment” is intended to mean a judgment made by acaregiver (e.g. physician, nurse, nurse practitioner, etc. in the caseof humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

The term “inverse agonists” is intended to mean moieties that bind theendogenous form of the receptor or to the constitutively activated formof the receptor, and which inhibit the baseline intracellular responseinitiated by the active form of the receptor below the normal base levelof activity which is observed in the absence of agonists or partialagonists, or decrease GTP binding to membranes. Preferably, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 30%, more preferably by at least 50%, and mostpreferably by at least 75%, as compared with the baseline response inthe absence of the inverse agonist.

The term “isolated” refers to material that is removed from its originalenvironment (e.g., the natural environment if it is naturallyoccurring). For example, a metabolite that is formed from a parentcompound present in a natural system (e.g. individual) is not isolated,but the same metabolite, separated from some or all of the coexistingmaterials in the natural system is considered isolated. In addition, themetabolite that is prepared by synthetic means is also consideredisolated.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates and hydrates of compounds of Formula (Ia); whereby thecomposition is amenable to investigation for a specified, efficaciousoutcome in a mammal (for example, without limitation, a human). Those ofordinary skill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system (e.g., in vivo in an individual, andthe like) generates a compound of Formula (Ia), wherein R^(4a) andR^(4b) are both H, as a result of chemical reaction(s), enzyme catalyzedchemical reaction(s), and/or metabolic chemical reaction(s). In someembodiments, compounds of the present invention can be converted to“pro-drugs.” In some embodiments, “pro-drugs” refer to compounds thathave been modified with specific chemical groups known in the art andwhen administered into an individual these groups undergobiotransformation to give the parent compound. Pro-drugs can thus beviewed as compounds of the invention containing one or more specializednon-toxic protective groups used in a transient manner to alter or toeliminate a property of the compound. In one general aspect, the“pro-drug” approach is utilized to facilitate oral absorption. Athorough discussion is provided in T. Higuchi and V. Stella, “Pro-drugsas Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; andin Bioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which arehereby incorporated by reference in their entirety.

The term “divalent-metabolically-labile group” as used herein refers toany group that comprises R^(4a) and R^(4b) together with the nitrogen towhich they are bonded and following administration of a compoundcontaining the group, is converted in vivo to a compound of Formula (Ia)wherein R^(4a) and R^(4b) are both H. The conversion of the “secondmetabolically-liable group” can be by metabolic and/or chemicalprocesses and can occur in one step or through a series of two or moresteps. Representative examples of a “divalent-metabolically-labilegroup” include, but are not limited to, when R^(4a) and R^(4b) togetherwith the nitrogen to which they are both bonded form a heterocyclicgroup optionally substituted with 1, 2, 3, 4, or 5 substituents selectedindependently from the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl, thiooxo, andsulfonamide (such as, morpholin-4-yl, 2,5-dioxo-pyrrolidin-1-yl, and thelike). The groups illustrated are exemplary, not exhaustive, and oneskilled in the art could prepare other known varieties of groups. Insome cases, a “divalent-metabolically-labile group” (i.e., related towhen R^(4a) and R^(4b) together with the nitrogen to which they are bothbonded) can serve to improve efficacy or safety through improved oralbioavailability, or pharmacodynamic half-life, etc.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Chemical Group, Moiety or Radical:

The term directly preceeding the chemical group beginning with “C”followed directly by a subscript number or a subscript range of numbersrefers to the number of carbons associated with the chemical group. Forexample, the term “C₁₋₆” in the chemical group “C₁₋₆ alkyl” refers to analkyl group containing one, two, three, four, five, or six carbons, andall possible isomers.

The term “C₁₋₁₂ acyl” denotes a C₁₋₁₂ alkyl radical attached to acarbonyl wherein alkyl has the same definition as described herein, someembodiments are when acyl is C₁₋₆ acyl, some embodiments are when acylis C₁₋₅ acyl; some examples include, but are not limited to, acetyl,propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e.,pivaloyl), pentanoyl and the like.

The term “C₁₋₁₂ acyloxy” denotes an acyl radical attached to an oxygenatom wherein acyl has the same definition has described herein; someembodiments are when acyloxy is C₁₋₁₁ acyloxy, some embodiments are whenacyloxy is C₁₋₁₀ acyloxy, some embodiments are when acyloxy is C₁₋₈acyloxy, some embodiments are when acyloxy is C₁₋₆ acyloxy, someembodiments are when acyloxy is C₁₋₅ acyloxy, some embodiments are whenacyloxy is C₁₋₄ acyloxy, some embodiments are when acyloxy is C₁₀₋₁₂acyloxy, some embodiments are when acyloxy is C₈₋₁₀ acyloxy. Someexamples include, but are not limited to, acetyloxy, propionyloxy,butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy,pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy,decanoyloxy, undecanoyloxy, dodecanoyloxy, and the like.

The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present, someembodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, andsome embodiments have 2 carbons. Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls. Accordingly, if more than one double bond is present thenthe bonds may be all E or Z or a mixtures of E and Z. Examples of analkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl and the like.

The term “C₁₋₆ alkoxy” as used herein denotes an alkyl radical, asdefined herein, attached directly to an oxygen atom. Examples includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “C₁₋₆ alkoxycarbonylamino” denotes the group represented by theformula:

wherein C₁₋₆ alkyl has the same definition as found herein. Examples ofC₁₋₆ alkoxycarbonylamino include methoxycarbonylamino,ethoxycarbonylamino, isopropoxycarbonylamino, propoxycarbonylamino,tert-butoxycarbonylamino, butoxycarbonylamino, and the like.

The term “C₁₋₈ alkyl” denotes a straight or branched carbon radicalcontaining 1 to 8 carbons, some embodiments are 1 to 6 carbons, someembodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, andsome embodiments are 1 or 2 carbons. Examples of an alkyl include, butare not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl,1-methylbutyl [i.e., —CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e.,—CH₂CH(CH₃)CH₂CH₃], n-hexyl and the like.

The term “C₁₋₆ alkylcarboxamido” or “C₁₋₆ alkylcarboxamide” denotes asingle C₁₋₆ alkyl group attached to the nitrogen of an amide group,wherein alkyl has the same definition as found herein. The C₁₋₆alkylcarboxamido may be represented by the following:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁₋₄ alkylene” refers to a C₁₋₄ divalent straight carbon groupcontaining 1 to 4 carbons, some embodiments are 1 to 3 carbons, someembodiments are 1 to 2 carbons. In some embodiments alkylene refers to,for example, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

The term “C₁₋₆ alkylsulfinyl” denotes a C₁₋₆ alkyl radical attached to asulfoxide radical of the formula: —S(O)— wherein the alkyl radical hasthe same definition as described herein. Examples include, but are notlimited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,iso-butylsulfinyl, t-butylsulfinyl, and the like.

The term “C₁₋₆ alkylsulfonamide” refers to the groups shown below:

wherein C₁₋₆ alkyl has the same definition as described herein.

The term “C₁₋₆ alkylsulfonyl” denotes a C₁₋₆ alkyl radical attached to asulfone radical of the formula: —S(O)₂— wherein the alkyl radical hasthe same definition as described herein. Examples include, but are notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, t-butylsulfonyl, and the like.

The term “C₁₋₆ alkylthio” denotes a C₁₋₆ alkyl radical attached to asulfide of the formula: —S— wherein the alkyl radical has the samedefinition as described herein. Examples include, but are not limitedto, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, n-propylsulfanyl,iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,iso-butylsulfanyl, t-butylsulfanyl, and the like.

The term “C₁₋₆ alkylthiocarboxamide” denotes a thioamide of thefollowing formulae:

wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₆ alkylureyl” denotes the group of the formula: —NC(O)N—wherein one or both of the nitrogens are substituted with the same ordifferent C₁₋₆ alkyl group wherein alkyl has the same definition asdescribed herein. Examples of an alkylureyl include, but are not limitedto, CH₃NHC(O)NH—, NH₂C(O)NCH₃—, (CH₃)₂NC(O)NH—, (CH₃)₂NC(O)NH—,(CH₃)₂NC(O)NCH₃—, CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6 carbons andat least one carbon-carbon triple bond, some embodiments are 2 to 4carbons, some embodiments are 2 to 3 carbons, and some embodiments have2 carbons. Examples of an alkynyl include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl”includes di- and tri-ynes.

The term “amino” denotes the group —NH₂.

The term “C₁₋₆ alkylamino” denotes one alkyl radical attached to anamino radical wherein the alkyl radical has the same meaning asdescribed herein. Some examples include, but are not limited to,methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,sec-butylamino, iso-butylamino, t-butylamino, and the like. Someembodiments are “C₁₋₂ alkylamino.”

The term “aryl” denotes a 6- to 12-membered mono- or bicyclic ringsystem containing only ring carbons wherein at least one ring isaromatic. Examples include phenyl, 1,2,3,4-tetrahydro-naphthalen-1-yl,1,2,3,4-tetrahydro-naphthalen-2-yl, 5,6,7,8-tetrahydro-naphthalen-1-yl,5,6,7,8-tetrahydro-naphthalen-2-yl, indan-4-yl, naphtha-1-yl,naphtha-2-yl, and the like.

The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—, —CH₂CH₂—and the like, which is further substituted with an aryl group. Examplesof an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to thenitrogen of an amide group, wherein aryl has the same definition asfound herein. The example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “bicyclic” refers to two C₄₋₇ cyclalkyl groups that share tworing carbons thus forming either a fused or bridged ring. Bicyclicexamples include, but not limited to, bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, and the like.

The term “carbo-C₁₋₆-alkoxy” refers to a C₁₋₆ alkyl ester of acarboxylic acid, wherein the alkyl group is as defined herein. Examplesinclude, but are not limited to, carbomethoxy, carboethoxy,carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy,carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-iso-pentoxy,carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “C₄₋₇ cycloalkenyl” denotes a non-aromatic ring radicalcontaining 4 to 7 ring carbons and at least one double bond; someembodiments contain 4 to 6 carbons; some embodiments contain 4 to 5carbons; some embodiments contain 4 carbons. Examples includecyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.

The term “C₃₋₁₀ cycloalkyl” denotes a saturated monocyclic, bicyclic, ortricyclic ring radical containing 3 to 8 carbons; some embodimentscontain 3 to 7 carbons; some embodiments contain 3 to 6 carbons; someembodiments contain 3 to 5 carbons; some embodiments contain 5 to 7carbons; some embodiments contain 3 to 4 carbons. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, bicyclo[2.2.1]heptyl, and the like.

The term “C₃₋₇ cycloalkylcarbonyl” denotes a C₃₋₇ cycloalkyl group, asdescribed herein, bonded to the carbon of a carbonyl group (i.e.,—C(═O)—). Examples of the C₃₋₇ cycloalkylcarbonyl group include, but notlimited to, cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl, and the like.

The term “C₃₋₆ cycloalkylene” refers to a divalent cycloalkyl radical,where cycloalkyl is as defined herein, containing 3 to 6 carbons; someembodiments contain 3 to 5 carbons; some embodiments contain 3 to 4carbons. In some embodiments, the C₃₋₆ cycloalkylene group has the twobonding groups on the same ring carbon, for example:

In some embodiments, the C₃₋₆ cycloalkylene group has the two bondinggroups on different ring carbons. It is understood that when the twogroups of the C₃₋₆ cycloalkylene group are on different ring carbonsthey may be cis or trans or mixtures thereof with respect to each other.

The term “C₂₋₈ dialkylamino” denotes an amino substituted with two ofthe same or different C₁₋₄ alkyl radicals wherein alkyl radical has thesame definition as described herein. Some examples include, but are notlimited to, dimethylamino, methylethylamino, diethylamino,methylpropylamino, methylisopropylamino, ethylpropylamino,ethylisopropylamino, dipropylamino, propylisopropylamino and the like.Some embodiments are “C₂₋₄ dialkylamino.”

The term “C₂₋₈ dialkylcarboxamido” or “C₂₋₈ dialkylcarboxamide” denotestwo alkyl radicals, that are the same or different, attached to an amidegroup, wherein alkyl has the same definition as described herein. A C₂₋₈dialkylcarboxamido may be represented by the following groups:

wherein C₁₋₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but are not limited to,N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

The term “C₂₋₈ dialkylsulfonamide” refers to one of the following groupsshown below:

wherein C₁₋₄ has the same definition as described herein, for examplebut are not limited to, methyl, ethyl, n-propyl, isopropyl, and thelike.

The term “C₂₋₈ dialkylthiocarboxamido” or “C₂₋₈ dialkylthiocarbox-amide”denotes two alkyl radicals, that are the same or different, attached toa thioamide group, wherein alkyl has the same definition as describedherein. A C₂₋₈ dialkylthiocarboxamido or C₂₋₈ dialkylthiocarboxamide maybe represented by the following groups:

Examples of a dialkylthiocarboxamide include, but are not limited to,N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “formyl” refers to the group —CHO.

The term “C₁₋₆ haloalkoxy” denotes a C₁₋₆ haloalkyl, as defined herein,which is directly attached to an oxygen atom. Examples include, but arenot limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

The term “C₁₋₆ haloalkyl” denotes an C₁₋₆ alkyl group, defined herein,wherein the alkyl is substituted with one halogen up to fullysubstituted and a fully substituted C₁₋₆ haloalkyl can be represented bythe formula C_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3, 4,5 or 6; when more than one halogen is present then they may be the sameor different and selected from the group consisting of F, Cl, Br and I,in some embodiments, the halogen is F. Examples of haloalkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl and the like.

The term “C₁₋₆ haloalkylcarboxamide” denotes an C₁₋₆ alkylcarboxamidegroup, defined herein, wherein the alkyl is substituted with one halogenup to fully substituted represented by the formula C_(n)L_(2n+1) whereinL is a halogen and “n” is 1, 2, 3, 4, 5 or 6. When more than one halogenis present they may be the same or different and selected from the groupconsisting of F, Cl, Br and I, preferably F.

The term “C₁₋₆ haloalkylsulfinyl” denotes a C₁₋₆ haloalkyl radicalattached to a sulfoxide group of the formula: —S(O)— wherein thehaloalkyl radical has the same definition as described herein. Examplesinclude, but are not limited to, trifluoromethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.

The term “C₁₋₆ haloalkylsulfonyl” denotes a C₁₋₆ haloalkyl radicalattached to a sulfone group of the formula: —S(O)₂— wherein haloalkylhas the same definition as described herein. Examples include, but arenot limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2-difluoroethylsulfonyl and the like.

The term “C₁₋₆ haloalkylthio” denotes a C₁₋₆ haloalkyl radical directlyattached to a sulfur wherein the haloalkyl has the same meaning asdescribed herein. Examples include, but are not limited to,trifluoromethylthio (i.e., CF₃S—, also referred to astrifluoromethylsulfanyl), 1,1-difluoroethylthio,2,2,2-trifluoroethylthio and the like. The term “halogen” or “halo”denotes to a fluoro, chloro, bromo or iodo group.

The term “heteroaryl” denotes a 6- to 12-membered mono- or bicyclic ringsystem wherein at least one ring atom is a heteroatom and at least onering is aromatic. Examples of a heteroatom include, O, S, N and the thelike. In some embodiments, N is optionally substituted, for example, H,or C₁₋₄ alkyl. Examples of heteroaryl groups include, but are notlimited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl,triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl,isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolyl, indolyl,1H-benzoimidazol-2-yl, benzo[1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, 2,3-dihydro-benzofurn-7-yl,2,3-dihydro-indol-1-yl, and the like. Other examples include, but arenot limited to, those in TABLE 1, TABLE 2, and the like.

The term “heterobicyclic” denotes a non-aromatic bicyclic ring, asdescribed herein, wherein 1, 2, or 3 ring carbons are replaced with aheteroatom selected from, but are not limited to, the group consistingof O, S, S(═O), S(═O)₂, and NH, wherein the nitrogen can be optionallysubstituted, and 1 or 2 ring carbons can be optionally substituted withoxo or thiooxo thus together form a carbonyl or thiocarbonyl grouprespectively. Examples of a heterobicyclic group include, but are notlimited to, 2,5-diaza-bicyclo[2.2.1]hept-2-yl,7-aza-bicyclo[2.2.1]hept-7-yl, and the like.

The term “heterocyclic” denotes a 3- to 12-membered mono- or bicyclicnon-aromatic ring system wherein at least one ring atom is a heteroatom.In some embodiments, heteroatom is selected from, but are not limitedto, the group consisting of O, S, S(═O), S(═O)₂, NH, wherein the N ofthe heterocyclic can be optionally substituted as described herein, insome embodiments, the nitrogen is optionally substituted with C₁₋₄ acylor C₁₋₄ alkyl, and ring carbon atoms optionally substituted with oxo ora thiooxo thus forming a carbonyl or thiocarbonyl group. Theheterocyclic group can be bonded at any available ring atom, forexample, ring carbon, ring nitrogen, and the like. In some embodiments,the heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered containingring. Examples of a heterocyclic group include, but are not limited to,aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl,azetidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,piperzin-1-yl, piperzin-2-yl, piperzin-3-yl, piperzin-4-yl,pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl,thiomorpholin-4-yl, [1,4]oxazepan-4-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl,azepan-4-yl, octahydro-quinolin-1-yl, octahydro-isoquinolin-2-yl, andthe like.

The term “hydroxyl” refers to the group —OH.

The term “nitro” refers to the group —NO₂.

As used herein, the term “oxo” refers to the substituent ═O,accordingly, when a carbon is substituted by an oxo group the new groupresulting from the carbon and oxo together is a carbonyl group.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term“sulfonic acid” refers to the group —SO₃H.

The term “thiol” denotes the group —SH.

Compounds of the Invention:

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;wherein R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷, R⁸, V, W, X, and Z havethe same definitions as described herein, supra and infra.

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia) wherein:

R^(4a) is H; and

R^(4b) is H, C₁₋₁₂ acyl, carbo-C₁₋₆-alkoxy, or C(═O)O-aryl, wherein theC₁₋₁₂ acyl, carbo-C₁₋₆-alkoxy, and —C(═O)O-aryl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected independentlyfrom the group consisting of C₁₋₆ alkylcarboxamide, amino, C₁₋₆alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, halogen, nitro, and phenyl;

or R^(4b) is —C(═O)OCR^(a)R^(b)OC(═O)R^(c), wherein R^(a), R^(b) andR^(c) are each independently selected from H, or C₁₋₆ alkyl.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, that are isolated.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, that are isolated outside the body ofan individual.

In some embodiments, isolated compounds of Formula (Ia) have a purity ofgreater than about 0.1%, about 1%, about 5%, about 10%, about 15%, about20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, about 98%, or about 99%.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, or a pharmaceutically acceptablesalt, hydrate, solvate, or N-oxide thereof.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷, R⁸, V, W, X, Z, etc.) containedwithin the generic chemical formulae described herein [e.g. (Ia), (Ic),(IC), etc.] are specifically embraced by the present invention just asif they were explicitly disclosed, to the extent that such combinationsembrace compounds that are stable compounds (ie., compounds that can beisolated, characterized and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables, as well as all subcombinations ofuses and medical indications described herein, are also specificallyembraced by the present invention just as if each of such subcombinationof chemical groups and subcombination of uses and medical indicationswere explicitly disclosed herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers, and the like. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. It is understood that the various tautomeric forms arewithin the scope of the compounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of the present inventionmay have one or more chiral centers, and therefore can exist asenantiomers and/or diastereomers. The invention is understood to extendto and embrace all such enantiomers, diastereomers and mixtures thereof,including but not limited, to racemates. Accordingly, some embodimentsof the present invention pertain to compounds of the present inventionthat are R enantiomers. Further, some embodiments of the presentinvention pertain to compounds of the present invention that are Senantiomers. In examples where more than one chiral center is present,then, some embodiments of the present invention include compounds thatare RS or SR enantiomers. In further embodiments, compounds of thepresent invention are RR or SS enantiomers. It is understood thatcompounds of the present invention are intended to represent allpossible individual enantiomers and mixtures thereof just as if each hadbeen individually named with the structure provided, unless stated orshown otherwise.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ic):

wherein each variable in Formula (Ic) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ie):

wherein each variable in Formula (Ie) has the same meaning as describedherein, supra and infra.

In some embodiments, X is O.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ig):

wherein each variable in Formula (Ig) has the same meaning as describedherein, supra and infra.

In some embodiments, X is S.

In some embodiments, V is O.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ik):

wherein each variable in Formula (Ik) has the same meaning as describedherein, supra and infra.

In some embodiments, V is NH.

In some embodiments, X is O and V is O.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Im):

wherein each variable in Formula (Im) has the same meaning as describedherein, supra and infra.

In some embodiments, X is O and V is NH.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Io):

wherein each variable in Formula (Io) has the same meaning as describedherein, supra and infra.

In some embodiments, W is —CH₂CH₂— optionally substituted with 1 to 2substituents selected independently from the group consisting of C₁₋₃alkyl, C₃₋₇ cycloalkyl, C₁₋₃ haloalkyl, oxo and imino, wherein the C₁₋₃alkyl is optionally substituted with C₁₋₃ alkylsulfonyl.

In some embodiments, W is —CH₂CH₂— optionally substituted with 1 to 2substituents selected independently from the group consisting of —CH₃,cyclohexyl, —CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxoand imino

In some embodiments, W is —CH₂CH₂—.

In some embodiments, Z is absent.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ip):

wherein each variable in Formula (Ip) has the same meaning as describedherein, supra and infra.

In some embodiments, Z is —CH₂— or —CH₂CH₂— each optionally substitutedwith 1 or 2 substituents selected independently from the groupconsisting of C₁₋₄ alkoxy and oxo.

In some embodiments, Z is —CH₂—, —C(═O)—, —CH₂CH₂—, or —CH(OCH₃)—.

In some embodiments, R¹ is C₁₋₆ alkyl.

In some embodiments, R¹ is —CH₃.

In some embodiments, R₁ is H.

It is understood when R₁ is H that tautomers are possible. It is wellunderstood and appreciated in the art that pyrazoles can exist invarious tautomeric forms. Two possible tautomeric forms are illustratedbelow:

It is further understood that tautomeric forms can also havecorresponding nomenclature for each represented tautomer, for example,the pyrazol-3-yl groups in Formula (Ir) and Formula (It) can berepresented by the general chemical names 1H-pyrazol-3-yl and2H-pyrazol-3-yl respectively. Therefore, the present invention includesall tautomers and the various nomenclature designations.

In some embodiments, R² is H.

In some embodiments, R³ is H or halogen.

In some embodiments, R³ is H, Cl, or Br.

In some embodiments, R^(4a) is H.

In some embodiments, R^(4a) and R^(4b) are both H.

In some embodiments, R^(4a) is H, and R^(4b) is C₁₋₁₂ acyl.

In some embodiments, R^(4a) is H, and R^(4b) is carbo-C₁₋₆-alkoxy.

In some embodiments, R^(4a) is H, and R^(4b) is—C(═O)OCR^(a)R^(b)OC(═O)R^(c), wherein R^(a), R^(b) and R^(c) are eachindependently selected from H or CH₃.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is H.

In some embodiments, R⁵, R⁶, and R⁷ are each H.

In some embodiments, R⁸ is aryl optionally substituted with 1, 2, 3, or4 substituents selected independently from the group consisting of C₁₋₆acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₈ dialkylamino,cyano, C₃₋₇ cycloalkyloxy, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, andheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted withheterocyclyl.

In some embodiments, R⁸ is phenyl or naphthyl each optionallysubstituted with 1, 2, 3, or 4 substituents selected independently fromthe group consisting of —C(═O)CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —CH₃,—CH₂CH₃, —NHC(═O)CH₃, —N(CH₃)₂, cyano, —O-cyclopentyl, F, Cl, Br,—OCH₂CF₃, —OCF₃, —OCF₂CF₃, —CF₃, thiophen-2-yl, and1,1-dioxo-1λ⁶-thiomorpholin-4-yl-CH₂—.

In some embodiments, R⁸ is selected from the group consisting of phenyl,2-chloro-phenyl, 3-methyl-phenyl, 4-chloro-phenyl, 2,4-difluoro-phenyl,3,4-difluoro-phenyl, 2-methoxy-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,3,4-dichloro-phenyl, 2-methyl-phenyl, 4-trifluoromethyl-phenyl,2-ethoxy-phenyl, 3-chloro-phenyl, 3-trifluoromethyl-phenyl,3,4-dimethoxy-phenyl, 2-trifluoromethyl-phenyl,3-fluoro-4-methoxy-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl,2,6-difluoro-phenyl, 3-methoxy-phenyl, and 4-methyl-phenyl.

In some embodiments, R⁸ is selected from the group consisting of2-morpholin-4-yl-phenyl, 3-dimethylamino-phenyl, 3-methoxy-phenyl,4-dimethylamino-phenyl, 4-trifluoromethoxy-phenyl,2-dimethylamino-phenyl, 4-cyano-phenyl,3-cyclopentyloxy-4-methoxy-phenyl, 4-methoxy-3-methyl-phenyl,4-methoxy-2-methyl-phenyl, 4-ethyl-phenyl, 4-thiophen-2-yl-phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl,4-fluoro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-methoxy-phenyl,3-ethoxy-phenyl, 2-fluoro-4-methoxy-phenyl, 4-fluoro-3-methoxy-phenyl,4-isopropoxy-phenyl, 3,5-difluoro-phenyl, 4-trifluoromethyl-phenyl,2,6-difluoro-4-methoxy-phenyl, 2,2-dimethyl-2,3-dihydro-benzofuran-7-yl,3-trifluoromethyl-phenyl, 4-methoxy-3-trifluoromethyl-phenyl,4-bromo-phenyl, 3-methoxy-4-methyl-phenyl, 3-methoxy-2-methyl-phenyl,4-chloro-phenyl, 2-bromo-5-methoxy-phenyl, 2-fluoro-3-methoxy-phenyl,4-bromo-3-methyl-phenyl, naphthalen-2-yl, 2,4-difluoro-phenyl,3-chloro-phenyl, 2-cyano-phenyl, 4-methyl-phenyl,5-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl, phenyl,2,4,5-trifluoro-3-methoxy-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,3-bromo-4-methoxy-phenyl, 3-fluoro-5-trifluoromethyl-phenyl,2-fluoro-5-trifluoromethyl-phenyl, 3-bromo-phenyl,3-fluoro-4-methoxy-phenyl, 3-cyano-phenyl, 2,6-difluoro-phenyl,4-methoxy-3,5-dimethyl-phenyl, 3-chloro-4-methoxy-phenyl,3,4,5-trimethoxy-phenyl, 2-fluoro-5-methoxy-phenyl,3-trifluoromethoxy-phenyl, 4-acetylamino-phenyl,3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl,3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,3-fluoro-4-trifluoromethyl-phenyl, 3,4-difluoro-phenyl,2-chloro-6-fluoro-phenyl,4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenyl, 2-methoxy-phenyl,4-acetyl-phenyl, and 8-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl.

In some embodiments, R⁸ is GA-alkyl.

In some embodiments, R⁸ is ethyl or t-buyl.

In some embodiments, R⁸ is heterocyclyl optionally substituted withsubstituents selected independently from the group consisting of C₁₋₆alkoxy, halogen, heteroaryl, and phenyl, wherein the C₁₋₆ alkyl,heteroaryl, and phenyl are each optionally substituted with 1substituent selected independently from the group consisting of C₁₋₆alkoxy, halogen, and C₁₋₆ haloalkyl.

In some embodiments, R⁸ is selected from the group consisting ofoctahydro-quinolin-1-yl, octahydro-isoquinolin-2-yl,4-pyridin-2-yl-piperazin-1-yl,4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl,4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl,4-(2-methoxy-phenyl)-piperazin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl,4-(4-methoxy-phenyl)-piperazin-1-yl, 2,5-dihydro-pyrrol-1-yl,4-methyl-piperazin-1-yl, 5,6-dihydro-4H-pyrimidin-1-yl, andtetrahydro-furan-2-yl.

In some embodiments, R⁸ is heteroaryl optionally substituted withsubstituents selected independently from the group consisting C₁₋₆alkoxy, and halogen.

In some embodiments, R⁸ is selected from the group consisting of4-chloro-2,3-dihydro-indol-1-yl, 3,4-dihydro-2H-quinolin-1-yl,2,3-dihydro-indol-1-yl, 1,3-dihydro-isoindol-2-yl,5-chloro-2,3-dihydro-indol-1-yl, 5-bromo-2,3-dihydro-indol-1-yl,6-chloro-2,3-dihydro-indol-1-yl, 6-fluoro-2,3-dihydro-indol-1-yl,6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl,3,4-dihydro-1H-isoquinolin-2-yl, and2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl.

In some embodiments, R⁸ is heteroaryl optionally substituted withsubstituents selected independently from the group consisting of C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₁₋₆ alkylthio, cyano, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkyl, hydroxyl, heterocyclyl, phenyl, andphenoxy, and the phenyl is optionally substituted with halogen.

In some embodiments, R⁸ is heteroaryl optionally substituted withsubstituents selected independently from the group consisting of —OCH₃,—OCH₂CH₃, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —C(CH₃)₃,—NHC(═O)CH₃, —SCH₃, cyano, cyclopropyl, F, Cl, Br, —CF₃, hydroxyl,morpholin-4-yl, heterocyclyl, phenyl, and phenoxy, and the phenyl isoptionally substituted with halogen.

In some embodiments, heteroaryl is a 5-membered heteroaryl, for example,a 5-membered heteroaryl as shown in TABLE 1:

TABLE 1

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring, for example, a imidazolyl ring can be bonded at one of thering nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group).

In some embodiments, heteroaryl is a 6-membered heteroaryl, for example,a 6-membered heteroaryl as shown in TABLE 2:

TABLE 2

wherein the heteroaryl group is bonded at any ring carbon.

In some embodiments, R⁸ is selected from the group consisting of2,2-difluoro-benzo[1,3]dioxol-5-yl,4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl,2,2-difluoro-benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl,2,3-dihydro-benzo[1,4]dioxin-5-yl, benzotriazol-5-yl,4-methyl-thiazol-5-yl, 5-isopropyl-isoxazol-3-yl, thiazol-4-yl,4-methyl-oxazol-5-yl, 1-methyl-1H-imidazol-4-yl,3,5-dimethyl-1H-pyrrol-2-yl, 2-ethyl-5-methyl-2H-pyrazol-3-yl,1-methyl-5-trifluoromethyl-1H-pyrazol-4-yl, 5-methyl-isoxazol-4-yl,4-chloro-1-methyl-1H-pyrazol-3-yl, 3-methyl-isoxazol-4-yl,5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl, 1-methyl-1H-pyrrol-2-yl,5-ethyl-4-fluoro-1H-pyrazol-3-yl, 3-ethoxy-thiophen-2-yl,5-butyl-4-fluoro-1H-pyrazol-3-yl, thiophen-2-yl,4-fluoro-5-methyl-1H-pyrazol-3-yl,1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl, 3-pyridinyl,1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl, 5-methyl-isoxazol-3-yl,3-methyl-benzofuran-2-yl, 4,5-dichloro-isothiazol-3-yl,3-chloro-5-fluoro-benzo[b]thiophen-2-yl, 2,5-dimethyl-2H-pyrazol-3-yl,3-chloro-benzo[b]thiophen-2-yl, 2,5-dichloro-thiophen-3-yl,4-methyl-thiophen-2-yl, 3-chloro-thiophen-2-yl,3-methyl-3H-imidazol-4-yl, 4-bromo-thiophen-2-yl,5-tert-butyl-2-methyl-2H-pyrazol-3-yl, 6-morpholin-4-yl-pyridin-3-yl,1-tert-butyl-5-methyl-1H-pyrazol-3-yl, 5-methyl-thiophen-2-yl,5-methyl-2-trifluoromethyl-furan-3-yl, 2-phenoxy-pyridin-3-yl,5-methyl-pyrazin-2-yl, 6-oxo-1,6-dihydro-pyridazin-3-yl, quinolin-2-yl,5 methyl pyridin 3 yl, 4,5-dimethyl-furan-2-yl,2,4-dimethyl-thiazol-5-yl, 2-bromo-4-methyl-thiazol-5-yl,5-bromo-pyridin-3-yl, 3-fluoro-pyridin-4-yl, pyridin-4-yl, pyridin-3-yl,pyridin-2-yl, thiophen-3-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl,1H-indol-2-yl, 2-methyl-pyridin-3-yl, 6-pyrrolidin-1-yl-pyridin-3-yl,6-phenoxy-pyridin-3-yl, 1H-imidazol-4-yl, 6 methyl pyridin 3 yl,2,6-dimethoxy-pyridin-3-yl, 4-chloro-pyridin-3-yl,1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl, 6-oxo-6H-pyran-3-yl,cinnolin-4-yl, 5-methyl-2H-pyrazol-3-yl,3-chloro-6-fluoro-benzo[b]thiophen-2-yl, 2-hydroxy-pyridin-3-yl,6-methyl-pyridin-2-yl, 3-chloro-pyridin-4-yl, 4-methoxy-thiophen-3-yl,6-oxo-1,6-dihydro-pyridin-3-yl, 5-methyl-1H-pyrazol-3-yl,4-chloro-1-ethyl-1H-pyrazol-3-yl, 5-bromo-furan-2-yl,4-bromo-1-methyl-1H-pyrazol-3-yl, 1,5-dimethyl-1H-pyrazol-3-yl,5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-yl,3,5-dichloro-pyridin-4-yl, 1-phenyl-5-trifluoromethyl-1H-pyrazol-3-yl,3,5-dimethyl-isoxazol-4-yl, 3-methyl-thiophen-2-yl,5-isopropyl-2H-pyrazol-3-yl, 6-trifluoromethyl-pyridin-3-yl,2-oxo-1,2-dihydro-pyridin-3-yl, 2-ethoxy-pyridin-3-yl,benzo[c]isoxazol-3-yl, 6-acetylamino-pyridin-3-yl,2-methylsulfanyl-pyridin-3-yl, 6-cyano-pyridin-3-yl,5-phenyl-isoxazol-3-yl,5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl,5-chloro-thiophen-2-yl, 2,5-dimethyl-furan-3-yl, furan-2-yl,5-tert-butyl-2-methyl-furan-3-yl, 3-phenyl-isoxazol-5-yl, isoxazol-5-yl,4-methyl-[1,2,3]oxadiazol-5-yl, and 2-methyl-furan-3-yl.

In some embodiments, R⁸ is benzo[d]isoxazol-3-yl, thiophen-3-yl,1H-indol-3-yl, 3,5-dimethyl-pyrazol-1-yl, or 5-methyl-tetrazol-1-yl.

In some embodiments, R⁸ is C₃₋₁₀ cycloalkyl optionally substituted withsubstituents selected independently from the group consisting of C₁₋₆alkoxy, halogen, and C₁₋₆ haloalkyl.

In some embodiments, R⁸ is 3-methoxy-cyclohexyl,bicyclo[2.2.1]hept-2-yl, 4-methoxy-cyclohexyl, 2,2-difluoro-cyclopropyl,cyclohexyl, cyclopentyl, 4-trifluoromethyl-cyclohexyl, cyclopropyl,4,4-difluroro-cyclohexyl, or adamantanyl.

In some embodiments, R⁸ is 3-methoxy-cyclohexyl, 4-methoxy-cyclohexyl,2,2-difluoro-cyclopropyl, cyclohexyl, cyclopentyl,4-trifluoromethyl-cyclohexyl, cyclopropyl, or 4,4-difluroro-cyclohexyl.

In some embodiments, R⁸ is 3-methoxy-cyclohexyl, 4-methoxy-cyclohexyl,cyclohexyl, 4-trifluoromethyl-cyclohexyl, or 4,4-difluroro-cyclohexyl.

In some embodiments, R⁸ is 2,2-difluoro-cyclopropyl, cyclopentyl, orcyclopropyl.

In some embodiments, R⁸ is bicyclo[2.2.1]hept-2-yl or adamantanyl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa):

wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of C₁₋₃ alkyl, C₃₋₇ cycloalkyl,C₁₋₃ haloalkyl, oxo and imino, wherein the C₁₋₃ alkyl is optionallysubstituted with C₁₋₃ alkylsulfonyl;

Z is absent; or Z is —CH₂— or —CH₂CH₂— each optionally substituted with1 or 2 substituents selected independently from the group consisting ofC₁₋₄ alkoxy and oxo;

R³ is H or halogen;

R^(4b) is H, C₁₋₁₂ acyl, or carbo-C₁₋₆-alkoxy, wherein the C₁₋₅ acyl,and carbo-C₁₋₆-alkoxy are each optionally substituted with halogen;

or

R^(4b) is —C(═O)OCR^(a)R^(b)OC(═O)R^(c), wherein R^(a), R^(b) and R^(c)are each independently selected from H, or C₁₋₆ alkyl; and

R⁸ is C₁₋₈-alkyl, aryl, C₃₋₁₀ cycloalkyl, heteroaryl or heterocyclyleach optionally substituted with 1, 2, 3, or 4 substituents selectedindependently from the group consisting of C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₈ dialkylamino, C₁₋₆ alkylthio, cyano,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, halogen, C₁₋₆ haloalkoxy, C₁₋₆haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phenyl, and phenoxy,wherein the C₁₋₆ alkyl and phenyl are each optionally substituted with 1substituent selected from heterocyclyl and halogen. Some embodiments ofthe present invention pertain to certain compounds of Formula (IIa)wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is —CH₂—, —C(═O)—, —CH₂CH₂—, or —CH(OCH₃)—;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is C₁₋₈-alkyl, aryl, C₃₋₁₀ cycloalkyl, heteroaryl or heterocyclyleach optionally substituted with 1, 2, 3, or 4 substituents selectedindependently from the group consisting of C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₈ dialkylamino, C₁₋₆ alkylthio, cyano,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, halogen, C₁₋₆ haloalkoxy, C₁₋₆haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phenyl, and phenoxy,wherein the C₁₋₆ alkyl and phenyl are each optionally substituted with 1substituent selected from heterocyclyl and halogen.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is —CH₂— or —CH₂CH₂—;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is selected from the group consisting of phenyl, 2-chloro-phenyl,3-methyl-phenyl, 4-chloro-phenyl, 2,4-difluoro-phenyl,3,4-difluoro-phenyl, 2-methoxy-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,3,4-dichloro-phenyl, 2-methyl-phenyl, 4-trifluoromethyl-phenyl,2-ethoxy-phenyl, 3-chloro-phenyl, 3-trifluoromethyl-phenyl,3,4-dimethoxy-phenyl, 2-trifluoromethyl-phenyl,3-fluoro-4-methoxy-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl,2,6-difluoro-phenyl, 3-methoxy-phenyl, and 4-methyl-phenyl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is absent;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is selected from the group consisting of 2-morpholin-4-yl-phenyl,3-dimethylamino-phenyl, 3-methoxy-phenyl, 4-dimethylamino-phenyl,4-trifluoromethoxy-phenyl, 2-dimethylamino-phenyl, 4-cyano-phenyl,3-cyclopentyloxy-4-methoxy-phenyl, 4-methoxy-3-methyl-phenyl,4-methoxy-2-methyl-phenyl, 4-ethyl-phenyl, 4-thiophen-2-yl-phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl,4-fluoro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-methoxy-phenyl,3-ethoxy-phenyl, 2-fluoro-4-methoxy-phenyl, 4-fluoro-3-methoxy-phenyl,4-isopropoxy-phenyl, 3,5-difluoro-phenyl, 4-trifluoromethyl-phenyl,2,6-difluoro-4-methoxy-phenyl, 2,2-dimethyl-2,3-dihydro-benzofuran-7-yl,3-trifluoromethyl-phenyl, 4-methoxy-3-trifluoromethyl-phenyl,4-bromo-phenyl, 3-methoxy-4-methyl-phenyl, 3-methoxy-2-methyl-phenyl,4-chloro-phenyl, 2-bromo-5-methoxy-phenyl, 2-fluoro-3-methoxy-phenyl,4-bromo-3-methyl-phenyl, naphthalen-2-yl, 2,4-difluoro-phenyl,3-chloro-phenyl, 2-cyano-phenyl, 4-methyl-phenyl,5-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl, phenyl,2,4,5-trifluoro-3-methoxy-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,3-bromo-4-methoxy-phenyl, 3-fluoro-5-trifluoromethyl-phenyl,2-fluoro-5-trifluoromethyl-phenyl, 3-bromo-phenyl,3-fluoro-4-methoxy-phenyl, 3-cyano-phenyl, 2,6-difluoro-phenyl,4-methoxy-3,5-dimethyl-phenyl, 3-chloro-4-methoxy-phenyl,3,4,5-trimethoxy-phenyl, 2-fluoro-5-methoxy-phenyl,3-trifluoromethoxy-phenyl, 4-acetylamino-phenyl,3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl,3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,3-fluoro-4-trifluoromethyl-phenyl, 3,4-difluoro-phenyl,2-chloro-6-fluoro-phenyl,4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenyl, 2-methoxy-phenyl,4-acetyl-phenyl, and 8-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂—;

Z is absent;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is selected from the group consisting of 2-morpholin-4-yl-phenyl,3-dimethylamino-phenyl, 3-methoxy-phenyl, 4-dimethylamino-phenyl,4-trifluoromethoxy-phenyl, 2-dimethylamino-phenyl, 4-cyano-phenyl,3-cyclopentyloxy-4-methoxy-phenyl, 4-methoxy-3-methyl-phenyl,4-methoxy-2-methyl-phenyl, 4-ethyl-phenyl, 4-thiophen-2-yl-phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl,4-fluoro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-methoxy-phenyl,3-ethoxy-phenyl, 2-fluoro-4-methoxy-phenyl, 4-fluoro-3-methoxy-phenyl,4-isopropoxy-phenyl, 3,5-difluoro-phenyl, 4-trifluoromethyl-phenyl,2,6-difluoro-4-methoxy-phenyl, 2,2-dimethyl-2,3-dihydro-benzofuran-7-yl,3-trifluoromethyl-phenyl, 4-methoxy-3-trifluoromethyl-phenyl,4-bromo-phenyl, 3-methoxy-4-methyl-phenyl, 3-methoxy-2-methyl-phenyl,4-chloro-phenyl, 2-bromo-5-methoxy-phenyl, 2-fluoro-3-methoxy-phenyl,4-bromo-3-methyl-phenyl, naphthalen-2-yl, 2,4-difluoro-phenyl,3-chloro-phenyl, 2-cyano-phenyl, 4-methyl-phenyl,5-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl, phenyl,2,4,5-trifluoro-3-methoxy-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,3-bromo-4-methoxy-phenyl, 3-fluoro-5-trifluoromethyl-phenyl,2-fluoro-5-trifluoromethyl-phenyl, 3-bromo-phenyl,3-fluoro-4-methoxy-phenyl, 3-cyano-phenyl, 2,6-difluoro-phenyl,4-methoxy-3,5-dimethyl-phenyl, 3-chloro-4-methoxy-phenyl,3,4,5-trimethoxy-phenyl, 2-fluoro-5-methoxy-phenyl,3-trifluoromethoxy-phenyl, 4-acetylamino-phenyl,3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl,3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,3-fluoro-4-trifluoromethyl-phenyl, 3,4-difluoro-phenyl,2-chloro-6-fluoro-phenyl,4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenyl, 2-methoxy-phenyl,4-acetyl-phenyl, and 8-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is absent;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is selected from the group consisting of octahydro-quinolin-1-yl,octahydro-isoquinolin-2-yl, 4-pyridin-2-yl-piperazin-1-yl,4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl,4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl,4-(2-methoxy-phenyl)-piperazin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl,4-(4-methoxy-phenyl)-piperazin-1-yl, 2,5-dihydro-pyrrol-1-yl,4-methyl-piperazin-1-yl, and 5,6-dihydro-4H-pyrimidin-1-yl, andtetrahydro-furan-2-yl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is absent;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is selected from the group consisting of4-chloro-2,3-dihydro-indol-1-yl, 3,4-dihydro-2H-quinolin-1-yl,2,3-dihydro-indol-1-yl, 1,3-dihydro-isoindol-2-yl,5-chloro-2,3-dihydro-indol-1-yl, 5-bromo-2,3-dihydro-indol-1-yl,6-chloro-2,3-dihydro-indol-1-yl, 6-fluoro-2,3-dihydro-indol-1-yl,6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl,3,4-dihydro-1H-isoquinolin-2-yl, and2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is absent;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is selected from the group consisting of2,2-difluoro-benzo[1,3]dioxol-5-yl,4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl,2,2-difluoro-benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl,2,3-dihydro-benzo[1,4]dioxin-5-yl, benzotriazol-5-yl,4-methyl-thiazol-5-yl, 5-isopropyl-isoxazol-3-yl, thiazol-4-yl,4-methyl-oxazol-5-yl, 1-methyl-1H-imidazol-4-yl,3,5-dimethyl-1H-pyrrol-2-yl, 2-ethyl-5-methyl-2H-pyrazol-3-yl,1-methyl-5-trifluoromethyl-1H-pyrazol-4-yl, 5-methyl-isoxazol-4-yl,4-chloro-1-methyl-1H-pyrazol-3-yl, 3-methyl-isoxazol-4-yl,5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl, 1-methyl-1H-pyrrol-2-yl,5-ethyl-4-fluoro-1H-pyrazol-3-yl, 3-ethoxy-thiophen-2-yl,5-butyl-4-fluoro-1H-pyrazol-3-yl, thiophen-2-yl,4-fluoro-5-methyl-1H-pyrazol-3-yl,1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl, 3-pyridinyl,1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl, 5-methyl-isoxazol-3-yl,3-methyl-benzofuran-2-yl, 4,5-dichloro-isothiazol-3-yl,3-chloro-5-fluoro-benzo[b]thiophen-2-yl, 2,5-dimethyl-2H-pyrazol-3-yl,3-chloro-benzo[b]thiophen-2-yl, 2,5-dichloro-thiophen-3-yl,4-methyl-thiophen-2-yl, 3-chloro-thiophen-2-yl,3-methyl-3H-imidazol-4-yl, 4-bromo-thiophen-2-yl,5-tert-butyl-2-methyl-2H-pyrazol-3-yl, 6-morpholin-4-yl-pyridin-3-yl,1-tert-butyl-5-methyl-1H-pyrazol-3-yl, 5-methyl-thiophen-2-yl,5-methyl-2-trifluoromethyl-furan-3-yl, 2-phenoxy-pyridin-3-yl,5-methyl-pyrazin-2-yl, 6-oxo-1,6-dihydro-pyridazin-3-yl, quinolin-2-yl,5-methyl-pyridin-3-yl, 4,5-dimethyl-furan-2-yl,2,4-dimethyl-thiazol-5-yl, 2-bromo-4-methyl-thiazol-5-yl,5-bromo-pyridin-3-yl, 3-fluoro-pyridin-4-yl, pyridin-4-yl, pyridin-3-yl,pyridin-2-yl, thiophen-3-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl,1H-indol-2-yl, 2-methyl-pyridin-3-yl, 6-pyrrolidin-1-yl-pyridin-3-yl,6-phenoxy-pyridin-3-yl, 1H-imidazol-4-yl, 6-methyl-pyridin-3-yl,2,6-dimethoxy-pyridin-3-yl, 4-chloro-pyridin-3-yl,1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl, 6-oxo-6H-pyran-3-yl,cinnolin-4-yl, 5-methyl-2H-pyrazol-3-yl,3-chloro-6-fluoro-benzo[b]thiophen-2-yl, 2-hydroxy-pyridin-3-yl,6-methyl-pyridin-2-yl, 3-chloro-pyridin-4-yl, 4-methoxy-thiophen-3-yl,6-oxo-1,6-dihydro-pyridin-3-yl, 5-methyl-1H-pyrazol-3-yl,4-chloro-1-ethyl-1H-pyrazol-3-yl, 5-bromo-furan-2-yl,4-bromo-1-methyl-1H-pyrazol-3-yl, 1,5-dimethyl-1H-pyrazol-3-yl,5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-yl,3,5-dichloro-pyridin-4-yl, 1-phenyl-5-trifluoromethyl-1H-pyrazol-3-yl,3,5-dimethyl-isoxazol-4-yl, 3-methyl-thiophen-2-yl,5-isopropyl-2H-pyrazol-3-yl, 6-trifluoromethyl-pyridin-3-yl,2-oxo-1,2-dihydro-pyridin-3-yl, 2-ethoxy-pyridin-3-yl,benzo[c]isoxazol-3-yl, 6-acetylamino-pyridin-3-yl,2-methylsulfanyl-pyridin-3-yl, 6-cyano-pyridin-3-yl,5-phenyl-isoxazol-3-yl,5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl,5-chloro-thiophen-2-yl, 2,5-dimethyl-furan-3-yl, furan-2-yl,5-tert-butyl-2-methyl-furan-3-yl, 3-phenyl-isoxazol-5-yl, isoxazol-5-yl,4-methyl-[1,2,3]oxadiazol-5-yl, and 2-methyl-furan-3-yl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of —CH₃, cyclohexyl,—CH₂CH₂S(═O)₂CH₃, cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;

Z is absent or —CH₂—;

R³ is H, Cl, or Br;

R^(4b) is H; and

R⁸ is 3-methoxy-cyclohexyl, bicyclo[2.2.1]hept-2-yl,4-methoxy-cyclohexyl, 2,2-difluoro-cyclopropyl, cyclohexyl, cyclopentyl,4-trifluoromethyl-cyclohexyl, cyclopropyl, 4,4-difluroro-cyclohexyl, andadamantanyl.

In some embodiments, a compound of the present invention is other than acompound of Formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;

wherein:

V² is O, S, S(═O), S(═O)₂ or NR³⁰;

W² is C₁₋₄ alkylene optionally substituted with 1 to 8 substituentsselected independently from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; or W is absent;

X² is C(═O), C(═S) or absent;

Y² is O, NR³¹ or absent;

Z² is C₁₋₄ alkylene, or C₃₋₆ cycloalkylene, each optionally substitutedwith 1 to 8 substituents selected independently from the groupconsisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl,halogen, hydroxyl, and oxo; or Z is absent;

R²¹ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₃₋₇ cycloalkyl;

R²² is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol, nitro andsulfonamide;

R²³ is selected from the group consisting of H, C₂₋₆ alkenyl, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofthe C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;

R²⁴ is heterobicyclic, heterocyclic, or heteroaryl each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,C₃₋₇ cycloalkylcarbonyl, C₂₋₆ dialkylcarboxamide, formyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, hydroxyl, nitro,phenyl and sulfonamide; wherein the C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy, andheteroaryl are each optionally substituted with substituents selectedindependently from the group consisting of C₁₋₆ alkyl, C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, andphenyl;

R²⁵, R²⁶, and R²⁷ are each selected independently from the groupconsisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy,C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋6 alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl;

R²⁸ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇ cycloalkyl, or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋6 alkylamino, C₂₋₈ dialkylamino,C₁₋₆ alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic, hydroxyl, thiol,nitro, phenoxy and phenyl, or two adjacent substituents together withthe aryl or the heteroaryl form a C₅₋₇ cycloalkyl optionally comprising1 to 2 oxygen atoms and optionally substituted with F, Cl or Br; andwherein the C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,C₁₋₆ alkylimino, C₂₋₈ dialkylamino, heterocyclic, and phenyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents selectedindependently from the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,thiol and nitro; and

R²⁹, R³⁰, and R³¹ are each independently H or C₁₋₈ alkyl.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following table:

Cmpd No. Chemical Structure Chemical Name  1

2,2-Difluoro- benzo[1,3]dioxole-5- carboxylic acid [4-((R)-2-amino-propoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  2

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3,5-dichloro-isonicotinamide  3

2,4-Dimethyl-thiazole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  4

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-morpholin-4-yl- benzamide  5

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3- dimethylamino- benzamide  6

2,2-Difluoro- benzo[1,3]dioxole-5- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  7

N-[4-((R)-2-Amino- propoxy)-3-(2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide  8

3-Methoxy- cyclohexanecarboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  9

4,5-Dimethyl-furan-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  10

4-Methyl-3,4-dihydro- 2H-benzo[1,4]oxazine- 7-carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  11

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4- dimethylamino- benzamide  12

5-(4-Chloro-phenyl)-2- trifluoromethyl-furan-3- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  13

N-[4-((R)-2-Amino- propoxy)-3-(2-methyl- 2H-pyrazol-3-yl)- phenyl]-4-trifluoromethoxy- benzamide  14

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(5-methyl-tetrazol-1-yl)- acetamide  15

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-5-methyl- nicotinamide  16

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-dimethylamino- benzamide  17

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2-cyano- benzamide  18

1-(4-Chloro-phenyl)-5- trifluoromethyl-1H- pyrazole-4-carboxylic acid[4-(2-amino- ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-phenyl]-amide  19

2,5-Dichloro-thiophene- 3-carboxylic acid [4- ((R)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-amide  20

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-oxo-2-p-tolyl-acetamide  21

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3- cyclopentyloxy-4- methoxy-benzamide  22

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-methoxy-3-methyl- benzamide  23

Quinoline-2-carboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide  24

1,5-Dimethyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  25

2,2-Difluoro- benzo[1,3]dioxole-4- carboxylic acid [4-((S)-2-amino-propoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  26

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-methoxy-phenyl)-2-oxo- acetamide  27

Octahydro-quinoline-1- carboxylic acid [4-(2- amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  28

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-methoxy-2-methyl- benzamide  29

6-Oxo-1,6-dihydro- pyridazine-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  30

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-methoxy-3- methyl-benzamide  31

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-ethyl- benzamide  32

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-fluoro-phenyl)-2-oxo- acetamide  33

Benzo[1,3]dioxole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  34

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2- phenyl-acetamide  35

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-thiophen-2-yl- benzamide  36

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2- fluoro-benzamide  37

Adamantane-1- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  38

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2-chloro-phenyl)- acetamide  39

Pyridine-2-carboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide  40

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- fluoro-benzamide  41

Octahydro-isoquinoline- 2-carboxylic acid [4-(2- amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  42

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-m-tolyl-acetamide  43

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-nicotinamide  44

4-Pyridin-2-yl- piperazine-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  45

4,5-Dichloro- isothiazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  46

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-(1,1,2,2- tetrafluoro-ethoxy)- benzamide  47

5-Methyl-2- trifluoromethyl-furan-3- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  48

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4- fluoro-benzamide  49

3-Methyl-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  50

2,2-Difluoro- benzo[1,3]dioxole-5- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  51

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-isonicotinamide  52

6-Methyl-pyridine-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide  53

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-fluoro-3-trifluoromethyl- benzamide  54

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4- methoxy-benzamide  55

5-Methyl-isoxazole-3- carboxylic acid [4-((S)- 2-amino-2-cyclohexyl-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  56

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-ethoxy- benzamide  57

5-Methyl-isoxazole-3- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  58

5-Isopropyl-2H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  59

N-[4-((S)-2-Amino-4- methanesulfonyl- butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-2-fluoro-4- methoxy-benzamide  60

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-fluoro-3-methoxy-benzamide  61

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-fluoro- isonicotinamide  62

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-hydroxy-nicotinamide  63

2,5-Dichloro-thiophene- 3-carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  64

5-Methyl-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  65

2,2-Difluoro- benzo[1,3]dioxole-4- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  66

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-isopropoxy- benzamide  67

2,2-Difluoro- benzo[1,3]dioxole-4- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  68

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3,5-difluoro-benzamide  69

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4- trifluoromethyl- benzamide  70

5-Methyl-isoxazole-3- carboxylic acid [4-((S)- 2-amino-3-cyclohexyl-propoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  71

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-5-bromo- nicotinamide  72

N-[4-((S)-2-Amino-3- methyl-butoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide  73

3-Methyl-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide  74

5-Chloro-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  75

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2,6-difluoro-4-methoxy- benzamide  76

2,2-Difluoro- benzo[1,3]dioxole-4- carboxylic acid [4-((R)-2-amino-propoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  77

4-Bromo-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  78

3,5-Dimethyl-isoxazole- 4-carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  79

N-[4-((R)-2-Amino- propoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4- methoxy-benzamide  80

2,2-Dimethyl-2,3- dihydro-benzofuran-7- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  81

4-Chloro-2,3-dihydro- indole-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  82

3-Chloro-6-fluoro- benzo[b]thiophene-2- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  83

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-chloro-phenyl)- acetamide  84

4,5-Dichloro- isothiazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  85

5-Methyl-isoxazole-3- carboxylic acid [4-((R)- 2-amino-3-methyl-butoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  86

2-Bromo-4-methyl- thiazole-5-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  87

3-Methyl-benzofuran-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide  88

3-Ethoxy-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide  89

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethyl- benzamide  90

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-methoxy-3- trifluoromethyl- benzamide  91

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-bromo- benzamide  92

{2-[4-(3-Methoxy- benzoylamino)-2-(2- methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}- carbamic acid benzyl ester  93

1-Phenyl-5- trifluoromethyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide  94

5-Chloro-1-methyl-3- trifluoromethyl-1H- pyrazole-4-carboxylic acid[4-(2-amino- ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-phenyl]-amide  95

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-bicyclo[2.2.1]hept-2-yl- acetamide  96

5-tert-Butyl-2-methyl- 2H-pyrazole-3- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazole-3- yl)-phenyl]-amide  97

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-methyl-nicotinamide  98

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-methoxy-2- methyl-benzamide  99

4-(5-Trifluoromethyl- pyridin-2-yl)-piperazine- 1-carboxylic acid [4-(2-amino-ethoxy)-3-(4- bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 100

4-Methyl- [1,2,3]thiadiazole-5- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 101

3,5-Dimethyl-1H- pyrrole-2-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 102

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2,4-difluoro-phenyl)- acetamide 103

1H-Indole-2-carboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 104

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3,4-difluoro-phenyl)- acetamide 105

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-6-trifluoromethyl- nicotinamide 106

Isoxazole-5-carboxylic acid [4-(2-amino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- amide 107

1-Methyl-1H-imidazole- 4-carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 108

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-methoxy-4-methyl- benzamide 109

3,4-Dihydro-2H- quinoline-1-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 110

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-methoxy-2-methyl- benzamide 111

N-[4-(2-Amino-2- methyl-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro- benzamide 112

3-Phenyl-isoxazole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 113

4-Methyl-oxazole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 114

4-Bromo-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 115

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2-methoxy-phenyl)- acetamide 116

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-fluoro-3- methoxy-benzamide 117

N-[4-((S)-2-Amino-3,3- dimethyl-butoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 118

5-tert-Butyl-2-methyl- furan-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 119

Thiazole-4-carboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 120

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3-fluoro-phenyl)- acetamide 121

Benzo[1,3]dioxole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 122

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-bromo-5-methoxy-benzamide 123

4-(3,5-Dichloro-pyridin- 4-yl)-piperazine-1- carboxylic acid [4-(2-amino-ethoxy)-3-(4- bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 124

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-isonicotinamide 125

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-phenyl-acetamide 126

3-Methyl-3H-imidazole- 4-carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 127

2-Phenyl-5- trifluoromethyl-oxazole- 4-carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 128

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2-fluoro-3- methoxy-benzamide 129

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-bromo-3-methyl-benzamide 130

Furan-2-carboxylic acid [4-(2-amino-ethoxy)-3- (2-methyl-2H-pyrazol-3-yl)-phenyl]-amide 131

5-Isopropyl-isoxazole-3- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 132

3-Chloro-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 133

2,3-Dihydro-indole-1- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 134

6-Oxo-1,6-dihydro- pyridine-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 135

N-[4-(2-Amino-2- methyl-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-4- trifluoromethyl- benzamide 136

4-Methoxy- cyclohexanecarboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 137

4-Methyl-thiazole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 138

5-Methyl-isoxazole-3- carboxylic acid [4-((S)- 2-amino-propoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 139

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-benzo[1,3]dioxol-5-yl- acetamide 140

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-6-morpholin-4- yl-nicotinamide 141

N-[4-((S)-2-Amino-2- cyclohexyl-ethoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 142

2,5-Dimethyl-furan-3- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 143

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2-fluoro-phenyl)- acetamide 144

2-Ethyl-5-methyl-2H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 145

5-Methyl-isoxazole-4- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 146

N-[4- Carbamoylmethoxy-3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethyl- benzamide 147

4-(2-Methoxy-phenyl)- piperazine-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 148

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-benzo[d]isoxazol-3-yl- acetamide 149

(S)-2-Methoxymethyl- pyrrolidine-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 150

2,2-Difluoro- cyclopropanecarboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 151

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3,4-dichloro-phenyl)-2- methoxy-acetamide 152

Naphthalene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 153

4-(4-Methoxy-phenyl)- piperazine-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 154

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-o-tolyl-acetamide 155

4-Methyl-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 156

1,3-Dihydro-isoindole-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 157

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2,4-difluoro-benzamide 158

N-[4-((R)-2-Amino-2- cyclohexyl-ethoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 159

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- chloro-benzamide 160

5-Chloro-2,3-dihydro- indole-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 161

5-Methyl-isoxazole-3- carboxylic acid [4-((R)- 2-amino-4-methyl-pentyloxy)-3-(4-chloro- 2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 162

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-(2-methoxy-phenyl)- propionamide 163

4-Methoxy-thiophene-3- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 164

2,5-Dihydro-pyrrole-1- carboxylic acid [4-(2- amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 165

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)- acetamide 166

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-cyano-benzamide 167

Thiazole-4-carboxylic acid [4-(2-amino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- amide 168

Thiophene-3-carboxylic acid [4-(2-amino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- amide 169

N-[4- Carbamoylmethoxy-3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- methoxy-benzamide 170

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-trifluoromethoxy- benzamide 171

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2,2-dimethyl- propionamide 172

N-[4- Carbamimidoylmethoxy- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2-fluoro-4- methoxy-benzamide 173

5-Bromo-2,3-dihydro- indole-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 174

Tetrahydro-furan-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 175

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2-ethoxy-phenyl)- acetamide 176

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-methyl-benzamide 177

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4- chloro-benzamide 178

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3-chloro-phenyl)- acetamide 179

2,5-Dichloro-thiophene- 3-carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 180

6-Chloro-2,3-dihydro- indole-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 181

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-fluoro-benzamide 182

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-propionamide 183

6-Fluoro-2,3-dihydro- indole-1-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 184

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3-trifluoromethyl-phenyl)- acetamide 185

5-Methyl-isoxazole-3- carboxylic acid [4-((S)- 2-amino-4-methyl-pentyloxy)-3-(4-chloro- 2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 186

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-5-methoxy-2- (2,2,2-trifluoro-ethoxy)- benzamide 187

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2,3-dimethoxy-phenyl)- acetamide 188

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]- benzamide 189

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2,4,5-trifluoro- 3-methoxy-benzamide 190

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-fluoro-4-trifluoromethyl- benzamide 191

2,2-Difluoro- benzo[1,3]dioxole-5- carboxylic acid [4-((S)-2-amino-propoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 192

1-Methyl-3- trifluoromethyl-1H- pyrazole-4-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 193

4-Bromo-1-methyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 194

N-[4-(2-Acetylamino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-3-methoxy-benzamide 195

3-Ethoxy-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 196

6,7-Dimethoxy-3,4- dihydro-1H- isoquinoline-2- carboxylic acid [4-(2-amino-ethoxy)-3-(4- bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 197

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-fluoro-3- trifluoromethyl- benzamide 198

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-bromo-4- methoxy-benzamide 199

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-fluoro-5-trifluoromethyl- benzamide 200

5-Ethyl-4-fluoro-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 201

5-Methyl-pyrazine-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 202

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-chloro-phenyl)-2-oxo- acetamide 203

2,3-Dihydro- benzo[1,4]dioxine-5- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 204

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-fluoro-5-trifluoromethyl- benzamide 205

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2-phenoxy- nicotinamide 206

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-methoxy-4- methyl-benzamide 207

5-Bromo-furan-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 208

N-[4-(2-Amiino-2- methyl-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo- benzamide 209

1-Methyl-1H-pyrrole-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 210

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2-trifluoromethyl-phenyl)- acetamide 211

Quinoline-2-carboxylic acid [4-(2-amino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- amide 212

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-fluoro-4- methoxy-benzamide 213

2-Oxo-1,2-dihydro- pyridine-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 214

5-Cyclopropyl-4-fluoro- 1H-pyrazole-3- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 215

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-thiophen-3-yl-acetamide 216

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-methoxy-2- methyl-benzamide 217

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-cyano-benzamide 218

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-thiophen-2-yl-benzamide 219

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2,6-difluoro-benzamide 220

5-Methyl-2- trifluoromethyl-furan-3- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 221

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-chloro-nicotinamide 222

4-Chloro-1-ethyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 223

4-Methyl-3,4-dihydro- 2H-benzo[1,4]oxazine- 7-carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 224

3-Methyl-isoxazole-4- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 225

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-(1H-indol-3-yl)- propionamide 226

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-methoxy-3,5- dimethyl-benzamide 227

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2-fluoro-4- methoxy-benzamide 228

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethyl- benzamide 229

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3-fluoro-4-methoxy- phenyl)-acetamide 230

(S)-N-[4-(2-Amino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-2-methoxy-2-phenyl- acetamide 231

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2,6-dimethoxy-nicotinamide 232

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-methoxy-phenyl)- acetamide 233

N-[4-((S)-2-Amino-3- methyl-butoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 234

4-Chloro-1-methyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 235

1-Methyl-1H-pyrrole-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 236

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-chloro-4- methoxy-benzamide 237

5-Methyl-1H-pyrazole- 3-carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 238

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide 239

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3,4,5-trimethoxy-benzamide 240

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-cyclohexyl- propionamide 241

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-6-methyl-nicotinamide 242

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4- methoxy-benzamide 243

5-(4-Chloro-phenyl)-2- trifluoromethyl-furan-3- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 244

5-Methyl-isoxazole-4- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 245

5-Methyl-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 246

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2-bromo-5- methoxy-benzamide 247

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(4-fluoro-phenyl)- acetamide 248

N-[4-((S)-2-Amino-4- methyl-pentyloxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 249

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-fluoro-5-methoxy-benzamide 250

3,4-Dihydro-2H- quinoline-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 251

1H-Imidazole-4- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 252

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-chloro-4-methoxy-benzamide 253

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-bromo-4-methoxy-benzamide 254

4,5-Dimethyl-furan-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 255

1-Methyl-5- trifluoromethyl-1H- pyrazole-4-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 256

1-tert-Butyl-5-methyl- 1H-pyrazole-3- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 257

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-6-phenoxy-nicotinamide 258

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-methoxy-3- trifluoromethyl- benzamide 259

Cyclopentanecarboxylic acid [4-(2-amino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- amide 260

5-Methyl-isoxazole-3- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 261

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(2,6-difluoro-phenyl)- acetamide 262

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3,5-dimethyl-pyrazol-1-yl)- acetamide 263

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-6-pyrrolidin-1- yl-nicotinamide 264

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(3-methoxy-phenyl)- acetamide 265

N-[4-(2-Amino-2- methyl-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro- phenyl)-acetamide 266

2-Methyl-furan-3- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 267

2-Ethyl-5-methyl-2H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 268

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-6-morpholin-4-yl- nicotinamide 269

3,4-Dihydro-1H- isoquinoline-2- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 270

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-fluoro-3-methoxy-benzamide 271

N-[4-(2-((R)-2-Amino-4- methyl-pentyloxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 272

3,5-Dimethyl-isoxazole- 4-carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 273

3-Methyl-benzofuran-2- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 274

Cyclopentanecarboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 275

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethoxy- benzamide 276

5-Methyl-isoxazole-3- carboxylic acid [4-[2- amino-2-(tetrahydro-pyran-4-yl)-ethoxy]-3- (4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]-amide 277

N-[4-((S)-2-Amino- propoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4- methoxy-benzamide 278

5-Isopropyl-2H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 279

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-fluoro-4-methoxy-benzamide 280

5-Methyl-2H-pyrazole- 3-carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 281

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- bromo-benzamide 282

1-Phenyl-5- trifluoromethyl-1H- pyrazole-4-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 283

5-tert-Butyl-2-methyl- 2H-pyrazole-3- carboxylic acid [4-(2-amino-ethoxy)-3-(4- chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 284

5-Methyl-1H-pyrazole- 3-carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 285

N-[4-((R)-2-Amino-3- methyl-butoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]- nicotinamide 286

N-[4-((S)-2-Amino- propoxy)-3-(2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 287

4-Acetylamino-N-[4-(2- amino-2-methyl- propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3- yl)-phenyl]-benzamide 288

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-cyclopentyloxy-4- methoxy-benzamide 289

Cinnoline-4-carboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 290

5-Phenyl-isoxazole-3- carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 291

1-(4-Chloro-phenyl)-5- trifluoromethyl-1H- pyrazole-4-carboxylic acid[4-(2-amino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 292

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3-fluoro-4- methyl-benzamide 293

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-fluoro-benzamide 294

2,3,4,5-Tetrahydro- benzo[b][1,4]diazepine- 1-carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 295

N-[4-((S)-2-Amino- propoxy)-3-(2-methyl- 2H-pyrazol-3-yl)- phenyl]-4-trifluoromethoxy- benzamide 296

4-Chloro-1-ethyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 297

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-(1H-indol-3-yl)-acetamide 298

4-Methyl-piperazine-1- carboxylic acid [4-(2- amino-ethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 299

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-6-cyano-nicotinamide 300

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-fluoro-4-methyl-benzamide 301

6-Oxo-6H-pyran-3- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 302

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-chloro-4-fluoro-benzamide 303

4-Trifluoromethyl- cyclohexanecarboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 304

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-chloro-3- fluoro-benzamide 305

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-2- methylsulfanyl- nicotinamide 306

Octahydro-isoquinoline- 2-carboxylic acid [4-(2- amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 307

2,5-Dichloro-thiophene- 3-carboxylic acid [4- ((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-amide 308

N-[4-(2-Amino-2- methyl-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethyl- benzamide 309

4-Fluoro-5-methyl-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 310

1H-Benzotriazole-5- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 311

6-Acetylamino-N-[4-(2- amino-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide 312

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-fluoro-4-trifluoromethyl- benzamide 313

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3,4-difluoro- benzamide 314

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-2-chloro-6-fluoro-benzamide 315

Thiophene-2-carboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 316

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-4-(1,1-dioxo- 1λ⁶-thiomorpholin-4- ylmethyl)-benzamide 317

Benzo[c]isoxazole-3- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 318

5-Butyl-4-fluoro-1H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 319

N-[4-(2-Amino-ethoxy)- 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-3,5-difluoro- benzamide 320

N-[4-(2-Amino-2- methyl-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethoxy- benzamide 321

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-4-methoxy-3,5-dimethyl- benzamide 322

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-methoxy-benzamide 323

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2- methoxy-benzamide 324

3-Chloro- benzo[b]thiophene-2- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 325

8-Methoxy-1,2,3,4- tetrahydro-naphthalene- 2-carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 326

4-Chloro-2,3-dihydro- indole-1-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 327

5-Methyl-isoxazole-3- carboxylic acid [4-((S)- 2-amino-3,3-dimethyl-butoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 328

Cyclopropanecarboxylic acid [4-(2-amino- ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 329

5,6-Dihydro-4H- pyrimidine-1-carboxylic acid [4-(2-amino-ethoxy)-3-(4-bromo-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 330

2,5-Dimethyl-2H- pyrazole-3-carboxylic acid [4-(2-amino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 331

4-Acetyl-N-[4-(2-amino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-benzamide 332

4,4-Difluoro- cyclohexanecarboxylic acid [4-(2-amino-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 333

3-Chloro-6-fluoro- benzo[b]thiophene-2- carboxylic acid [4-(2-amino-ethoxy)-3-(2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 334

3-Chloro-thiophene-2- carboxylic acid [4-(2- amino-ethoxy)-3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-phenyl]- amide 335

N-[4-(2-Amino-2- methyl-propoxy)-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- methoxy-benzamide 336

5-Methyl-isoxazole-3- carboxylic acid [4-((S)- 2-amino-2-cyclohexyl-ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3- yl)-phenyl]-amide 337

N-[4-(2-Amino-ethoxy)- 3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3-chloro-isonicotinamide 338

N-[4-(2-Amino-4,4,4- trifluoro-butoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2- fluoro-4-methoxy- benzamide 339

{2-[4-(3-Methoxy- benzoylamino)-2-(2- methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}- carbamic acid 4-nitro- phenyl ester 340

N-[4-[2-((S)-2- Acetylamino-4- methylsulfanyl- butyrylamino)-ethoxy]-3-(2-methyl-2H-pyrazol- 3-yl)-phenyl]-3- methoxy-benzamide 341

{2-[4-(3-Methoxy- benzoylamino)-2-(2- methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}- carbamic acid 2-chloro- ethyl ester 342

{2-[4-(3-Methoxy- benzoylamino)-2-(2- methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}- carbamic acid ethyl ester 343

{2-[4-(3-Methoxy- benzoylamino)-2-(2- methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}- carbamic acid 2- dimethylamino-ethyl ester 344

N-[4-[2-(2- Dimethylamino- acetylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-3-methoxy- benzamide 345

Acetic acid 1-{2-[-(3- methoxy- benzoylamino)-2-(2- methyl-2H-pyrazol-3-yl)-phenoxy]- ethylcarbamoyloxy}- ethyl ester 346

N-[4-(2-Hexanoylamino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-3-methoxy-benzamide

Additionally, individual compounds and chemical genera of the presentinvention, such as Formula (Ia) and related Formulae therefrom,encompass all pharmaceutically acceptable salts, solvates, andparticularly hydrates, thereof.

It is understood that the present invention embraces each diastereomer,each enantiomer and mixtures thereof of each compound and genericFormulae disclosed herein just as if they were each individuallydisclosed with the specific stereochemical designation for each chiralatom, for example carbon. Separation of the individual isomers (such as,chiral HPLC, recrystallization of diastereomeric mixture, and the like)or selective synthesis (such as, enantiomeric selective synthesis, andthe like) of the individual isomers is accomplished by application ofvarious methods which are well known to practitioners in the art.

The compounds of the Formula (Ia) of the present invention can beprepared according to the general synthetic schemes in FIGS. 1 through 8as well as relevant published literature procedures that are used by oneskilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter in the working Examples. Protection anddeprotection may be carried out by procedures generally known in the art(see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]; incorporated hereinby reference in its entirety).

Indications and Methods of Treatment

In addition to the foregoing beneficial uses for the modulators of5-HT_(2A) receptor activity disclosed herein, the compounds disclosedherein are believed to be useful in the treatment of several additionaldiseases and disorders, and in the amelioration of symptoms thereof.Without limitation, these include the following:

1. Antiplatelet Therapies (Conditions Related to Platelet Aggregation):

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (heart attack), the heart muscle does notreceive enough oxygen-rich blood as a result of a blockage in thecoronary blood vessels. If taken while an attack is in progress orimmediately afterward (preferably within 30 minutes), antiplatelets canreduce the damage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter based technique used to open arteriesobstructed by a blood clot. Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrythmia) Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

5-HT_(2A) receptors are expressed on smooth muscle of blood vessels and5-HT secreted by activated platelets causes vasoconstriction as well asactivation of additional platelets during clotting. There is evidencethat a 5-HT_(2A) inverse agonist will inhibit platelet aggregation andthus be a potential treatment as an antiplatelet therapy (see Satimura,K, et al., Clin Cardiol 2002 Jan. 25 (1):28-32; and Wilson, H. C et al.,Thromb Haemost 1991 Sep. 2; 66(3):355-60).

5-HT_(2A) inverse agonists can be used to treat, for example,claudication or peripheral artery disease as well as cardiovascularcomplications (see Br. Med. J. 298: 424-430, 1989), Arterial thrombosis(see, Pawlak, D. et al. Thrombosis Research 90: 259-270, 1998),atherosclerosis (see, Hayashi, T. et al. Atherosclerosis 168: 23-31,2003), vasoconstriction, caused by serotonin (see, Fujiwara, T. andChiba, S. Journal of Cardiovascular Pharmacology 26: 503-510, 1995),restenosis of arteries following angioplasty or stent placement (see,Fujita, M. et al. Am Heart J. 145:e16 2003). It can also be used aloneor in combination with thrombolytic therapy, for example, tPA (see,Yamashita, T. et al. Haemostasis 30:321-332, 2000), to providecardioprotection following MI or postischemic myocardial dysfunction(see, Muto, T. et al. Mol. Cell. Biochem. 272: 119-132, 2005) orprotection from ischemic injury during percutaneous coronaryintervention (see, Horibe, E. Circulation Research 68: 68-72, 2004), andthe like, including complications resulting therefrom.

5-HT_(2A) inverse antagonists can increase circulating adiponectin inpatients, suggesting that they would also be useful in protectingpatients against indications that are linked to adiponectin, forexample, myocardial ischemia reperfusion injury and artherosclerosis(see Nomura, Shosaku, et al. Blood Coagulation and Fibrinolysis 2005,16, 423-428).

The 5-HT_(2A) inverse agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereofcomprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein. In further embodiments, thepresent invention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein at a time where such riskexists.

One aspect of the present invention provides a therapeutic agent fortreating indications associated with the pathophysiology of plateletaggregation used in combination with compounds of the present inventionas disclosed herein. Accordingly, compounds of the present invention canbe used alone or in combination with other therapeutic agent(s), suchas, thromboxane A2 blocker (aspirin and the like), and ADP-mediatedplatelet aggregation inhibitor (ticlopidine, clopidogrel, and the like)either administered together or separately.

2. Asthma

5-HT (5-hydroxytryptamine) has been linked to the pathophysiology ofacute asthma (see Cazzola, M. and Matera, M. G., TIPS, 2000, 21, 13; andDe Bie, J. J. et al., British J. Pharm., 1998, 124, 857-864). Thecompounds of the present invention disclosed herein are useful in thetreatment of asthma, and the treatment of the symptoms thereof.Accordingly, in some embodiments, the present invention provides methodsfor treating asthma in a patient in need of the treatment, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein. In further embodiments, methods areprovided for treating a symptom of asthma in a patient in need of thetreatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

3. Agitation

Agitation is a well-recognized behavioral syndrome with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension and uncooperativeness (See Cohen-Mansfield J, and Billig, N.,(1986), Agitated Behaviors in the Elderly. I. A Conceptual Review. J AmGeriatr Soc 34(10): 711-721).

Agitation is a common occurrence in the elderly and often associatedwith dementia such as those caused by Alzheimer's disease, Lewy body,Parkinson's, and Huntington's, which are degenerative diseases of thenervous system and by diseases that affect blood vessels, such asstroke, or multi-infarct dementia, which is caused by multiple strokesin the brain can also induce dementia. Alzheimer's disease accounts forapproximately 50 to 70% of all dementias (See Koss E, et al., (1997),Assessing patterns of agitation in Alzheimer's disease patients with theCohen-Mansfield Agitation Inventory. The Alzheimer's Disease CooperativeStudy. Alzheimer Dis Assoc Disord 11 (suppl 2):S45-S50).

An estimated five percent of people aged 65 and older and up to 20percent of those aged 80 and older are affected by dementia; of thesesufferers, nearly half exhibit behavioral disturbances, such asagitation, wandering and violent outbursts.

Agitated behaviors can also be manifested in cognitively intact elderlypeople and by those with psychiatric disorders other than dementia.

Agitation is often treated with antipsychotic medications such ashaloperidol in nursing home and other assisted care settings. There isemerging evidence that agents acting at the 5-HT_(2A) receptors in thebrain have the effects of reducing agitation in patients, includingAlzheimer's dementia (See Katz, I. R., et al., J Clin Psychiatry 1999February, 60(2):107-115; and Street, J. S., et al., Arch Gen Psychiatry2000 October, 57(10):968-976).

The compounds of the invention disclosed herein are useful for treatingagitation and symptoms thereof. Thus, in some embodiments, the presentinvention provides methods for treating agitation in a patient in needof such treatment comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments, the agitation is due to a psychiatric disorder other thandementia. In some embodiments, the present invention provides methodsfor treatment of agitation or a symptom thereof in a patient sufferingfrom dementia comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments of such methods, the dementia is due to a degenerativedisease of the nervous system, for example and without limitation,Alzheimers disease, Lewy body, Parkinson's disease, and Huntington'sdisease, or dementia due to diseases that affect blood vessels,including, without limitation, stroke and multi-infarct dementia. Insome embodiments, methods are provided for treating agitation or asymptom thereof in a patient in need of such treatment, where thepatient is a cognitively intact elderly patient, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein.

4. Add-on Therapy to Haloperidol in the Treatment of Schizophrenia andOther Disorders:

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked by anumber of characteristics, psychotic symptoms, progression, phasicdevelopment and deterioration in social behavior and professionalcapability in the region below the highest level ever attained.Characteristic psychotic symptoms are disorders of thought content(multiple, fragmentary, incoherent, implausible or simply delusionalcontents or ideas of persecution) and of mentality (loss of association,flight of imagination, incoherence up to incomprehensibility), as wellas disorders of perceptibility (hallucinations), of emotions(superficial or inadequate emotions), of self-perception, of intentionsand impulses, of interhuman relationships, and finally psychomotoricdisorders (such as catatonia). Other symptoms are also associated withthis disorder. (See, American Statistical and Diagnostic Handbook).

Haloperidol (Haldol) is a potent dopamine D₂ receptor antagonist. It iswidely prescribed for acute schizophrenic symptoms, and is veryeffective for the positive symptoms of schizophrenia. In accordance withsome methods of the invention, adding a 5-HT_(2A) inverse agonistconcomitantly with Haldol will provide benefits including the ability touse a lower dose of Haldol without losing its effects on positivesymptoms, while reducing or eliminating its inductive effects onnegative symptoms, and prolonging relapse to the patient's nextschizophrenic event.

5. Sleep Disorders

It is reported in the National Sleep Foundation's 2002 Sleep In AmericaPoll, more than one-half of the adults surveyed (58%) report havingexperienced one or more symptoms of insomnia at least a few nights aweek in the past year. Additionally, about three in ten (35%) say theyhave experienced insomnia-like symptoms every night or almost everynight.

The normal sleep cycle and sleep architecture can be disrupted by avariety of organic causes as well as environmental influences. Accordingto the International Classification of Sleep Disorders, there are over80 recognized sleep disorders. Of these, compounds of the presentinvention are effective, for example, in any one or more of thefollowing sleep disorders (ICSD—International Classification of SleepDisorders: Diagnostic and Coding Manual. Diagnostic ClassificationSteering Committee, American Sleep Disorders Association, 1990):

A. Dyssomnias

a. Intrinsic Sleep Disorders:

Psychophysiological insomnia, Sleep state misperception, Idiopathicinsomnia, Obstructive sleep apnea syndrome, Central sleep apneasyndrome, Central alveolar hypoventilation syndrome, Periodic limbmovement disorder, Restless leg syndrome and Intrinsic sleep disorderNOS.

b. Extrinsic Sleep Disorders:

Inadequate sleep hygiene, Environmental sleep disorder, Altitudeinsomnia, Adjustment sleep disorder, Insufficient sleep syndrome,Limit-setting sleep disorder, SleepOnset association disorder, Nocturnaleating (drinking) syndrome, Hypnotic dependent sleep disorder,Stimulant-dependent sleep disorder, Alcohol-dependent sleep disorder,Toxin-induced sleep disorder and Extrinsic sleep disorder NOS.

c. Circadian Rhythm Sleep Disorders:

Time zone change (jet lag) syndrome, Shift work sleep disorder,Irregular sleep-wake pattern, Delayed sleep phase syndrome, Advancedsleep phase syndrome, Non-24-hour sleep-wake disorder and Circadianrhythm sleep disorder NOS.

B. Parasomnias

a. Arousal Disorders:

Confusional arousals, Sleepwalking and Sleep terrors.

b. Sleep-Wake Transition Disorders:

Rhythmic movement disorder, Sleep starts, Sleep talking and Nocturnalleg cramps.

C. Sleep Disorders Associated with Medical/Psychiatric Disorders

a. Associated with Mental Disorders:

Psychoses, Mood disorders, Anxiety disorders, Panic disorders andAlcoholism.

b. Associated with Neurological Disorders:

Cerebral degenerative disorders, Dementia, Parkinsonism, Fatal familialinsomnia, Sleep-related epilepsy, Electrical status epilepticus of sleepand Sleep-related headaches.

c. Associated with Other Medical Disorders:

Sleeping sickness, Nocturnal cardiac ischemia, Chronic obstructivepulmonary disease, Sleep-related asthma, Sleep-related gastroesophagealreflux, Peptic ulcer disease, Fibrositis syndrome, Osteoarthritis,Rheumatoid arthritis, Fibromyalgia and Post-surgical.

The effects of sleep deprivation are more than excessive daytimesleepiness. Chronic insomniacs report elevated levels of stress,anxiety, depression and medical illnesses (National Institutes ofHealth, National Heart, Lung, and Blood Institute, Insomnia Facts Sheet,October 1995). Preliminary evidence suggests that having a sleepdisorder that causes significant loss of sleep may contribute toincreased susceptibility to infections due to immunosuppression,cardiovascular complications such as hypertension, cardiac arrhythmias,stroke, and myocardial infarction, comprimised glucose tolerance,increased obesity and metabolic syndrome. Compounds of the presentinvention are useful to prevent or alleviate these complications byimproving sleep quality.

The most common class of medications for the majority of sleep disordersare the benzodiazepines, but the adverse effect profile ofbenzodiazepines include daytime sedation, diminished motor coordination,and cognitive impairments. Furthermore, the National Institutes ofHealth Consensus conference on Sleeping Pills and Insomnia in 1984 havedeveloped guidelines discouraging the use of such sedative-hypnoticsbeyond 4-6 weeks because of concerns raised over drug misuse,dependency, withdrawal and rebound insomnia. Therefore, it is desirableto have a pharmacological agent for the treatment of insomnia, which ismore effective and/or has fewer side effects than those currently used.In addition, benzodiazepines are used to induce sleep, but have littleto no effect on the maintenance of sleep, sleep consolidation or slowwave sleep. Therefore, sleep maintenance disorders are not currentlywell treated.

Clinical studies with agents of a similar mechanism of action as arecompounds of the present invention have demonstrated significantimprovements on objective and subjective sleep parameters in normal,healthy volunteers as well as patients with sleep disorders and mooddisorders [Sharpley A L, et al. Slow Wave Sleep in Humans. Role of5-HT_(2A) and 5HT_(2C) Receptors. Neuropharmacology, 1994, Vol.33(3/4):467-71; Winokur A, et al. Acute Effects of Mirtazapine on SleepContinuity and Sleep Architecture in Depressed Patients: A Pilot Study.Soc of Biol Psych, 2000, Vol. 48:75-78; and Landolt H P, et al.Serotonin-2 Receptors and Human Sleep: Effect of Selective Antagonist onEEG Power Spectra. Neuropsychopharmacology, 1999, Vol. 21(3):455-661

Some sleep disorders are sometimes found in conjunction with otherconditions and accordingly those conditions are treatable by compoundsof Formula (Ia). For example, but not limited to, patients sufferingfrom mood disorders typically suffer from a sleep disorder that can betreatable by compounds of Formula (Ia). Having one pharmacological agentwhich treats two or more existing or potential conditions, as does thepresent invention, is more cost effective, leads to better complianceand has fewer side effects than taking two or more agents.

It is an object of the present invention to provide a therapeutic agentfor the use in treating Sleep Disorders. It is another object of thepresent invention to provide one pharmaceutical agent, which may beuseful in treating two or more conditions wherein one of the conditionsis a sleep disorder. Compounds of the present invention described hereinmay be used alone or in combination with a mild sleep inducer, such as,a sedating antihistamine (diphenhydramine, chloropheniramine,bromopheniramine and the like), GABA-A receptor modulators (Ambien,Sonata, Indiplon, Gaboxadol, and the like), melatonin agonists (ML1receptor agonist, such as Ramelteon and the like), sedatingantidepressants (such as a tricyclic antidepressant, doxepine and thelike), and benzodiazepines (diazepam and the like) and eitheradministered together or separately.

Sleep Architecture:

Sleep comprises two physiological states: Non rapid eye movement (NREM)and rapid eye movement (REM) sleep. NREM sleep consists of four stages,each of which is characterized by progressively slower brain wavepatterns, with the slower patterns indicating deeper sleep. So calleddelta sleep, stages 3 and 4 of NREM sleep, is the deepest and mostrefreshing type of sleep. Many patients with sleep disorders are unableto adequately achieve the restorative sleep of stages 3 and 4. Inclinical terms, patients' sleep patterns are described as fragmented,meaning the patient spends a lot of time alternating between stages 1and 2 (semi-wakefulness) and being awake and very little time in deepsleep. As used herein, the term “fragmented sleep architecture” means anindividual, such as a sleep disorder patient, spends the majority oftheir sleep time in NREM sleep stages 1 and 2, lighter periods of sleepfrom which the individual can be easily aroused to a waking state bylimited external stimuli. As a result, the individual cycles throughfrequent bouts of light sleep interrupted by frequent awakeningsthroughout the sleep period. Many sleep disorders are characterized by afragmented sleep architecture. For example, many elderly patients withsleep complaints have difficulty achieving long bouts of deep refreshingsleep (NREM stages 3 and 4) and instead spend the majority of theirsleep time in NREM sleep stages 1 and 2.

In contrast to fragmented sleep architecture, as used herein the term“sleep consolidation” means a state in which the number of NREM sleepbouts, particularly Stages 3 and 4, and the length of those sleep boutsare increased, while the number and length of waking bouts aredecreased. In essence, the architecture of the sleep disorder patient isconsolidated to a sleeping state with increased periods of sleep andfewer awakenings during the night and more time is spent in slow wavesleep (Stages 3 and 4) with fewer oscillation Stage 1 and 2 sleep.Compounds of the present invention can be effective in consolidatingsleep patterns so that the patient with previously fragmented sleep cannow achieve restorative, delta-wave sleep for longer, more consistentperiods of time.

As sleep moves from stage 1 into later stages, heart rate and bloodpressure drop, metabolic rate and glucose consumption fall, and musclesrelax. In normal sleep architecture, NREM sleep makes up about 75% oftotal sleep time; stage 1 accounting for 5-10% of total sleep time,stage 2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%.About 90 minutes after sleep onset, NREM sleep gives way to the firstREM sleep episode of the night. REM makes up approximately 25% of totalsleep time. In contrast to NREM sleep, REM sleep is characterized byhigh pulse, respiration, and blood pressure, as well as otherphysiological patterns similar to those seen in the active waking stage.Hence, REM sleep is also known as “paradoxical sleep.” Sleep onsetoccurs during NREM sleep and takes 10-20 minutes in healthy youngadults. The four stages of NREM sleep together with a REM phase form onecomplete sleep cycle that is repeated throughout the duration of sleep,usually four or five times. The cyclical nature of sleep is regular andreliable; a REM period occurs about every 90 minutes during the night.However, the first REM period tends to be the shortest, often lastingless than 10 minutes, whereas the later REM periods may last up to 40minutes. With aging, the time between retiring and sleep onset increasesand the total amount of night-time sleep decreases because of changes insleep architecture that impair sleep maintenance as well as sleepquality. Both NREM (particularly stages 3 and 4) and REM sleep arereduced. However, stage 1 NREM sleep, which is the lightest sleep,increases with age.

As used herein, the term “delta power” means a measure of the durationof EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and isthought to be a measure of deeper, more refreshing sleep. Delta power ishypothesized to be a measure of a theoretical process called Process Sand is thought to be inversely related to the amount of sleep anindividual experiences during a given sleep period. Sleep is controlledby homeostatic mechanisms; therefore, the less one sleeps the greaterthe drive to sleep. It is believed that Process S builds throughout thewake period and is discharged most efficiently during delta power sleep.Delta power is a measure of the magnitude of Process S prior to thesleep period. The longer one stays awake, the greater Process S or driveto sleep and thus the greater the delta power during NREM sleep.However, individuals with sleep disorders have difficulty achieving andmaintaining delta wave sleep, and thus have a large build-up of ProcessS with limited ability to discharge this buildup during sleep. 5-HT_(2A)agonists tested preclinically and clinically mimic the effect of sleepdeprivation on delta power, suggesting that subjects with sleepdisorders treated with a 5-HT_(2A) inverse agonist or antagonist will beable to achieve deeper more refreshing sleep. These same effects havenot been observed with currently marketed pharmacotherapies. Inaddition, currently marketed pharmacotherapies for sleep have sideeffects such as hangover effects or addiction that are associated withthe GABA receptor. 5-HT_(2A) inverse agonists do not target the GABAreceptor and so these side effects are not a concern.

Subjective and Objective Determinations of Sleep Disorders:

There are a number of ways to determine whether the onset, duration orquality of sleep (e.g. non-restorative or restorative sleep) is impairedor improved. One method is a subjective determination of the patient,e.g., do they feel drowsy or rested upon waking. Other methods involvethe observation of the patient by another during sleep, e.g., how longit takes the patient to fall asleep, how many times does the patientwake up during the night, how restless is the patient during sleep, etc.Another method is to objectively measure the stages of sleep usingpolysomnography.

Polysomnography is the monitoring of multiple electrophysiologicalparameters during sleep and generally includes measurement of EEGactivity, electroculographic activity and electromyographic activity, aswell as other measurements. These results, along with observations, canmeasure not only sleep latency (the amount of time required to fallasleep), but also sleep continuity (overall balance of sleep andwakefulness) and sleep consolidation (percent of sleeping time spent indelta-wave or restorative sleep) which may be an indication of thequality of sleep.

There are five distinct sleep stages, which can be measured bypolysomnography: rapid eye movement (REM) sleep and four stages ofnon-rapid eye movement (NREM) sleep (stages 1, 2, 3 and 4). Stage 1 NREMsleep is a transition from wakefulness to sleep and occupies about 5% oftime spent asleep in healthy adults. Stage 2 NREM sleep, which ischaracterized by specific EEG waveforms (sleep spindles and Kcomplexes), occupies about 50% of time spent asleep. Stages 3 and 4 NREMsleep (also known collectively as slow-wave sleep and delta-wave sleep)are the deepest levels of sleep and occupy about 10-20% of sleep time.REM sleep, during which the majority of vivid dreams occur, occupiesabout 20-25% of total sleep.

These sleep stages have a characteristic temporal organization acrossthe night. NREM stages 3 and 4 tend to occur in the first one-third toone-half of the night and increase in duration in response to sleepdeprivation. REM sleep occurs cyclically through the night. Alternatingwith NREM sleep about every 80-100 minutes. REM sleep periods increasein duration toward the morning. Human sleep also variescharacteristically across the life span. After relative stability withlarge amounts of slow-wave sleep in childhood and early adolescence,sleep continuity and depth deteriorate across the adult age range. Thisdeterioration is reflected by increased wakefulness and stage 1 sleepand decreased stages 3 and 4 sleep.

In addition, the compounds of the invention can be useful for thetreatment of the sleep disorders characterized by excessive daytimesleepiness such as narcolepsy. Inverse agonists at the serotonin5-HT_(2A) receptor improve the quality of sleep at nightime which candecrease excessive daytime sleepiness.

Accordingly, another aspect of the present invention relates to thetherapeutic use of compounds of the present invention for the treatmentof Sleep Disorders. Compounds of the present invention are potentinverse agonists at the serotonin 5-HT_(2A) receptor and can beeffective in the treatment of Sleep Disorders by promoting one or moreof the following: reducing the sleep onset latency period (measure ofsleep induction), reducing the number of nighttime awakenings, andprolonging the amount of time in delta-wave sleep (measure of sleepquality enhancement and sleep consolidation) without effecting REMsleep. In addition, compounds of the present invention can be effectiveeither as a monotherapy or in combination with sleep inducing agents,for example but not limited to, antihistamines.

6. Diabetic-Related Pathologies:

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), increasedplasma serotonin concentration in diabetic patients has also beenimplicated to play a role in disease progression (Pietraszek, M. H., etal. Thrombosis Res. 1992, 66(6), 765-74; and Andrzejewska-Buczko J, etal., Klin Oczna. 1996; 98(2), 101-4). Serotonin is believed to play arole in vasospasm and increased platelet aggregability. Improvingmicrovascular blood flow is able to benefit diabetic complications.

A recent study by Cameron and Cotter in Naunyn Schmiedebergs ArchPharmacol. 2003 June; 367(6):607-14, used a 5-HT_(2A) antagonistexperimental drug AT-1015, and other nonspecific 5-HT_(2A) antagonistsincluding ritanserin and sarpogrelate. These studies found that allthree drugs were able to produce a marked correction (82.6-99.7%) of a19.8% sciatic motor conduction deficit in diabetic rats. Similarly,44.7% and 14.9% reductions in sciatic endoneurial blood flow andsaphenous sensory conduction velocity were completely reversed.

In a separate patient study, sarpogrelate was evaluated for theprevention of the development or progression of diabetic nephropathy(Takahashi, T., et al., Diabetes Res Clin Pract. 2002 November;58(2):123-9). In the trial of 24 months of treatment, sarpogrelatesignificantly reduced urinary albumin excretion level.

7. Glaucoma

Topical ocular administration of 5-HT₂ receptor antagonists result in adecrease in intra ocular pressure (IOP) in monkeys (Chang et al., J.Ocul Pharmacol 1:137-147 (1985)) and humans (Mastropasqua et al., ActaOphthalmol Scand Suppl 224:24-25 (1997)) indicating utility for similarcompounds such as 5-HT_(2A) inverse agonists in the treatment of ocularhypertension associated with glaucoma. The 5-HT₂ receptor antagonistketanserin (Mastropasqua supra) and sarpogrelate (Takenaka et al.,Investig Ophthalmol Vis Sci 36:S734 (1995)) have been shown tosignificantly lower IOP in glaucoma patients.

8. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a lethaldemyelinating disease caused by an opportunistic viral infection ofoligodendrocytes in immunocompromised patients. The causative agent isJC virus, a ubiquitous papovavirus that infects the majority of thepopulation before adulthood and establishes a latent infection in thekidney. In immunocompromised hosts, the virus can reactivate andproductively infect oligodendrocytes. This previously rare condition,until 1984 reported primarily in persons with underlyinglymphoproliferative disorders, is now more common because it occurs in4% of patients with AIDS. Patients usually present with relentlesslyprogressive focal neurologic defects, such as hemiparesis or visualfield deficits, or with alterations in mental status. On brain MRI, oneor more white matter lesions are present; they are hyperintense onT2-weighted images and hypointense on T1-weighted images. There is nomass effect, and contrast enhancement is rare. Diagnosis can beconfirmed by brain biopsy, with demonstration of virus by in situhybridization or immunocytochemistry. Polymerase chain reactionamplification of JC virus sequences from the CSF can confirm diagnosiswithout the need for biopsy [see, e.g., Antinori et al., Neurology(1997) 48:687-694; Berger and Major, Seminars in Neurology (1999)19:193-200; and Portegies, et al., Eur. J. Neurol. (2004) 11:297-304].Currently, there is no effective therapy. Survival after diagnosis isabout 3 to 5 months in AIDS patients.

JC virus enters cells by receptor-mediated clathrin-dependentendocytosis. Binding of JC virus to human glial cells (e.g.,oligodendrocytes) induces an intracellular signal that is critical forentry and infection by a ligand-inducible clathrin-dependent mechanism[Querbes et al., J Virology (2004) 78:250-256]. Recently, 5-HT_(2A) wasshown to be the receptor on human glial cells mediating infectious entryof JC virus by clathrin-dependent endocytosis [Elphick et al., Science(2004) 306:1380-1383]. 5-HT_(2A) antagonists, including ketanserin andritanserin, inhibited JC virus infection of human glial cells.Ketanserin and ritanserin have inverse agonist activity at 5-HT_(2A).

5-HT_(2A) antagonists including inverse agonists have been contemplatedto be useful in the treatment of PML [Elphick et al., Science (2004)306:1380-1383]. Prophylactic treatment of HIV-infected patients with5-HT_(2A) antagonists is envisioned to prevent the spread of JC virus tothe central nervous system and the development of PML. Aggressivetherapeutic treatment of patients with PML is envisioned to reduce viralspread within the central nervous system and prevent additional episodesof demyelination.

In some embodiments, methods are provided for treating progressivemultifocal leukoencephalopathy in a patient in need of such treatment,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein.

9. Hypertension

Serotonin has been observed to play an important role in the regulationof vascular tone, vasoconstriction, and pulmonary hypertension (see,Deuchar, G. et al. Pulm. Pharmacol. Ther. 18(1):23-31. 2005; and Marcos,E. et al. Circ. Res. 94(9):1263-70 2004). Ketanserin, a 5-HT_(2A)inverse agonist, have been demonstrated to protect against circulatoryshocks, intracranial hypertension, and cerebral ischemia duringheatstroke (see, Chang, C. et al. Shock 24(4): 336-340 2005); and tostabilize blood pressure in spontaneously hypertensive rats (see, Miao,C. Clin. Exp. Pharmacol. Physiol. 30(3): 189-193). Mainserin, a5-HT_(2A) inverse agonist, has been shown to prevent DOCA-salt inducedhypertension in rats (see, Silva, A. Eur, J. Pharmacol. 518(2-3): 152-72005).

10. Pain

5-HT_(2A) inverse agonists are also effective for the treatment of pain.Sarpogrelate has been observed to provide a significant analgesic effectboth on thermal induced pain in rats after intraperitonealadministration and on inflammatory pain in rats after either intrathecalor intraperitoneal administration (see, Nishiyama, T. Eur. J. Pharmacol.516:18-22 2005). This same 5-HT_(2A) inverse agonist in humans has beenshown to be an effective treatment for lower back pain, leg pain andnumbness associated with sciatica brought on by lumbar disc herniation(see, Kanayama, M. et al. J. Neurosurg: Spine 2:441-446 2005).

Representative Methods of the Invention:

One aspect of the present invention pertains to methods for modulatingthe activity of a 5-HT_(2A) serotonin receptor by contacting thereceptor with a compound according to any of the embodiments describedherein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of platelet aggregation in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of an indication selected from the group consisting ofcoronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, and atrial fibrillation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an individual suffering from atrialfibrillation, comprising administering to the individual in need thereofa therapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of asthma in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of a symptom of asthma in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of agitation or a symptom thereof in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition. In some embodiments,the individual is a cognitively intact elderly individual.

One aspect of the present invention pertains to methods for thetreatment of agitation or a symptom thereof in an individual sufferingfrom dementia comprising administering to the individual in need thereofa therapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition. In someembodiments, the dementia is due to a degenerative disease of thenervous system. In some embodiments, the dementia is Alzheimers disease,Lewy body, Parkinson's disease or Huntington's disease. In someembodiments, the dementia is due to diseases that affect blood vessels.In some embodiments, the dementia is due to stroke or multi-infarctdementia.

One aspect of the present invention pertains to methods for thetreatment of an individual suffering from at least one of theindications selected from the group consisting of behavioral disorder,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorder, organic or NOS psychosis, psychotic disorder,psychosis, acute schizophrenia, chronic schizophrenia and NOSschizophrenia comprising administering to the individual in need thereofa therapeutically effective amount of a dopamine D₂ receptor antagonistand a compound according to any of the embodiments described herein or apharmaceutical composition. In some embodiments, the dopamine D₂receptor antagonist is haloperidol.

One aspect of the present invention pertains to methods for thetreatment of an individual with infantile autism, Huntington's chorea,or nausea and vomiting from chemotherapy or chemotherapeutic antibodiescomprising administering to the individual in need thereof atherapeutically effective amount of a dopamine D₂ receptor antagonistand a compound according to any of the embodiments described herein or apharmaceutical composition. In some embodiments, the dopamine D₂receptor antagonist is haloperidol.

One aspect of the present invention pertains to methods for thetreatment of schizophrenia in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of adopamine D₂ receptor antagonist and a compound according to any of theembodiments described herein or a pharmaceutical composition. In someembodiments, the dopamine D₂ receptor antagonist is haloperidol.

One aspect of the present invention pertains to methods for thetreatment of alleviating negative symptoms of schizophrenia induced bythe administration of haloperidol to an individual suffering from theschizophrenia, comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical composition.In some embodiments, the haloperidol and the compound or pharmaceuticalcomposition are administered in separate dosage forms. In someembodiments, the haloperidol and the compound or pharmaceuticalcomposition are administered in a single dosage form.

One aspect of the present invention pertains to methods for thetreatment of a sleep disorder in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or apharmaceutical composition.

In some embodiments, the sleep disorder is a dyssomnia. In someembodiments, the dyssomnia is selected from the group consisting ofpsychophysiological insomnia, sleep state misperception, idiopathicinsomnia, obstructive sleep apnea syndrome, central sleep apneasyndrome, central alveolar hypoventilation syndrome, periodic limbmovement disorder, restless leg syndrome, inadequate sleep hygiene,environmental sleep disorder, altitude insomnia, adjustment sleepdisorder, insufficient sleep syndrome, limit-setting sleep disorder,sleep-onset association disorder, nocturnal eating or drinking syndrome,hypnotic dependent sleep disorder, stimulant-dependent sleep disorder,alcohol-dependent sleep disorder, toxin-induced sleep disorder, timezone change (jet lag) syndrome, shift work sleep disorder, irregularsleep-wake pattern, delayed sleep phase syndrome, advanced sleep phasesyndrome, and non-24-hour sleep-wake disorder.

In some embodiments, the sleep disorder is a parasomnia. In someembodiments, the parasomnia is selected from the group consisting ofconfusional arousals, sleepwalking and sleep terrors, rhythmic movementdisorder, sleep starts, sleep talking and nocturnal leg cramps. In someembodiments, the sleep disorder is characterized by excessive daytimesleepiness such as narcolepsy.

In some embodiments, the sleep disorder is associated with a medical orpsychiatric disorder. In some embodiments, the medical or psychiatricdisorder is selected from the group consisting of psychoses, mooddisorders, anxiety disorders, panic disorders, alcoholism, cerebraldegenerative disorders, dementia, parkinsonism, fatal familial insomnia,sleep-related epilepsy, electrical status epilepticus of sleep,sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia,chronic obstructive pulmonary disease, sleep-related asthma,sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositissyndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia andpost-surgical sleep disorder.

One aspect of the present invention pertains to methods for thetreatment of a diabetic-related disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

In some embodiments, the diabetic-related disorder is diabeticperipheral neuropathy.

In some embodiments, the diabetic-related disorder is diabeticnephropathy.

In some embodiments, the diabetic-related disorder is diabeticretinopathy.

One aspect of the present invention pertains to methods for thetreatment of glaucoma or other diseases of the eye with abnormalintraocular pressure.

One aspect of the present invention pertains to methods for thetreatment of progressive multifocal leukoencephalopathy in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

In some embodiments, the individual in need thereof has alymphoproliferative disorder. In some embodiments, thelymphoproliferative disorder is leukemia or lymphoma. In someembodiments, the leukemia or lymphoma is chronic lymphocytic leukemia,Hodgkin's disease, or the like.

In some embodiments, the individual in need thereof has amyeloproliferative disorder.

In some embodiments, the individual in need thereof has carcinomatosis.

In some embodiments, the individual in need thereof has a granulomatousor inflammatory disease. In some embodiments, the granulomatous orinflammatory disease is tuberculosis or sarcoidosis.

In some embodiments, the individual in need thereof isimmunocompromised. In some embodiments, the immunocompromised individualhas impaired cellular immunity. In some embodiments, the impairedcellular immunity comprises impaired T-cell immunity.

In some embodiments, the individual in need thereof is infected withHIV. In some embodiments, the HIV-infected individual has a CD4+ cellcount of ≦200/mm³. In some embodiments, the HIV-infected individual hasAIDS. In some embodiments, the HIV-infected individual has AIDS-relatedcomplex (ARC). In certain embodiments, ARC is defined as the presence oftwo successive CD4+ cell counts below 200/mm³ and at least two of thefollowing signs or symptoms: oral hairy leukoplakia, recurrent oralcandidiasis, weight loss of at least 2.5 kg or 10% of body weight withinlast six months, multidermatomal herpes zoster, temperature 38.5° C. formore than 14 consecutive days or more than 15 days in a 30-day period,or diarrhea with more than three liquid stools per day for at least 30days [see, e.g., Yamada et al., Clin. Diagn. Virol. (1993) 1:245-256].

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy. In some embodiments, the immunosuppressivetherapy comprises administering an immunosuppressive agent [see, e.g.,Mueller, Ann Thorac Surg (2004) 77:354-362; and Krieger and Emre,Pediatr Transplantation (2004) 8:594-599]. In some embodiments, theimmunosuppressive therapy comprises administering an immunosuppressiveagent selected from the group consisting of: corticosteroids (forexample, prednisone and the like), calcineurin inhibitors (for example,cyclosporine, tacrolimus, and the like), antiproliferative agents (forexample, azathioprine, mycophenolate mofetil, sirolimus, everolimus, andthe like), T-cell depleting agents (for example, OKT®3 monoclonalantibody (mAb), anti-CD3 immunotoxin FN18-CRM9, Campath-1H (anti-CD52)mAb, anti-CD4 mAb, anti-T cell receptor mAb, and the like), anti-IL-2receptor (CD25) mAb (for example, basiliximab, daclizumab, and thelike), inhibitors of co-stimulation (for example, CTLA4-Ig, anti-CD154(CD40 ligand) mAb, and the like), deoxyspergualin and analogs thereof(for example, 15-DSG, LF-08-0299, LF14-0195, and the like), leflunomideand analogs thereof (for example, leflunomide, FK778, FK779, and thelike), FTY720, anti-alpha-4-integrin monoclonal antibody, and anti-CD45RB monoclonal antibody. In some embodiments, the immunosuppressive agentand the compound or pharmaceutical composition are administered inseparate doseage forms. In some embodiments, the immunosuppressive agentand the compound or pharmaceutical composition are administered in asingle doseage form.

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy after organ transplantation. In someembodiments, the organ is liver, kidney, lung, heart, or the like [see,e.g., Singh et al., Transplantation (2000) 69:467-472].

In some embodiments, the individual in need thereof is undergoingtreatment for a rheumatic disease. In some embodiments, the rheumaticdisease is systemic lupus erythematosus or the like.

In some embodiments, the compound or the pharmaceutical compositioninhibits JC virus infection of human glial cells.

One aspect of the present invention pertains to methods for treatinghypertension in an individual comprising administering to the individualin need thereof a therapeutically effective amount of a compoundaccording to any embodiments described herein and a pharmaceuticallyacceptable carrier.

One aspect of the present invention pertains to methods for treatingpain in an individual comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany embodiments described herein and a pharmaceutically acceptablecarrier.

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a compound according any embodimentsdescribed herein and a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is selected from the groupconsisting of coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, and atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a blood clot formation in anangioplasty or coronary bypass surgery individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a blood clot formation in anindividual suffering from atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a symptom of asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is agitation or a symptomthereof in an individual. In some embodiments the individual is acognitively intact elderly individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is agitation or a symptomthereof in an individual suffering from dementia. In some embodimentsthe dementia is due to a degenerative disease of the nervous system. Insome embodiment the dementia is Alzheimers disease, Lewy body,Parkinson's disease, or Huntington's disease. In some embodiments thedementia is due to diseases that affect blood vessels. In someembodiments the dementia is due to stroke or multi-infarct dementia.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is selected from the group consisting of abehavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorder, psychosis, acute schizophrenia, chronicschizophrenia and NOS schizophrenia. In some embodiments the dopamine D₂receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is infantile autism, Huntington's chorea, or nauseaand vomiting from chemotherapy or chemotherapeutic antibodies. In someembodiments the dopamine D₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is schizophrenia. In some embodiments the dopamineD₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a negative symptom orsymptoms of schizophrenia induced by the administration of haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in a single dosage form.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is progressive multifocalleukoencephalopathy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method of treatment of thehuman or animal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof a 5-HT_(2A) associated disorder, as described herein, in the human oranimal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof a sleep disorder, as described herein, in the human or animal body bytherapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof platelet aggregation in the human or animal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof progressive multifocal leukoencephalopathy in the human or animalbody by therapy.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions, and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20th Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro, A. R., et al.).

While it is possible that, for use in the treatment, a compound of theinvention may, in an alternative use, be administered as a raw or purechemical, it is preferable however to present the compound or activeingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5-HT_(2A) receptormodulators. By the term “active ingredient” is defined in the context ofa “pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, as is customary and is known to the physician, it isto be tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but are not limited to, about 0.001 mgto about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg toabout 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg toabout 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or care-giver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, or whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well-known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and others,and, if appropriate, customary propellants, for example include carbondioxide, CFC's, such as, dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the 5-HT_(2A) receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as 5-HT_(2A)receptor modulators, for the treatment of a 5-HT_(2A) mediated diseaseor disorder in domestic animals (e.g., cats and dogs) and in otherdomestic animals (e.g., such as cows, chickens, fish, etc.). Those ofordinary skill in the art are readily credited with understanding theutility of such compounds in such settings.

Combination Therapy:

While the compounds of the present invention can be administered as thesole active pharmaceutical agent (i.e., mono-therapy), they can also beused in combination with other pharmaceutical agents (i.e.,combination-therapy) for the treatment of thediseases/conditions/disorders described herein. Accordingly, anotheraspect of the present invention includes methods of treatment of5-HT_(2A) serotonin receptor associated disorders diseases comprisingadministering to an individual in need of such treatment atherapeutically-effective amount of a compound of the present inventionin combination with one or more additional pharmaceutical agent asdescribed herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include other antiplatelet,antithrombotic or anticoagulant drugs, anti-arrhythmic agents,Cholesteryl ester transfer protein (CETP) inhibitors, Niacin or niacinanalogs, Adenosine or adenosine analogs, Nitroglycerin or nitrates,prothrombolytic agents, and the like. Other pharmaceutical agents,including the agents set forth infra, are well known or will be readilyapparent in light of the instant disclosure, to one of ordinary skill inthe art.

The compounds of the present invention can also be used in combinationwith other antiplatelet, antithrombotic or anticoagulant drugs such asthrombin inhibitors, platelet aggregation inhibitors such as aspirin,clopidogrel (Plavix®), ticlopidine or CS-747 {i.e., acetic acid5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylester and its active metabolite R-99224,(Z)-2-[1-[2-cyclopropyl-1(S)-(2-fluorophenyl)-2-oxoethyl]-4(R)-sulfanylpiperidin-3-ylidene]aceticacid}, abciximab (ReoPro®), eptifibatide (Integrilin®), tirofiban(Aggrastat®), warfarin, low molecular weight heparins (such as LOVENOX),GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 [i.e.,(3Z,6Z)-3-Benzylidene-6-(4-methoxybenzylidene)-1-methylpiperazine-2,5-dione]and T-686 [i.e.,3(E)-Benzylidene-4(E)-(3,4,5-trimethoxybenzylidene)pyrrolidine-2,5-dione],inhibitors of α-2-antiplasmin such as anti-α-2-antiplasmin antibody andthromboxane receptor antagonists (such as ifetroban), prostacyclinmimetics, phosphodiesterase (PDE) inhibitors, such as dipyridamole(Persantine®) or cilostazol, PDE inhibitors in combination withthromboxane receptor antagonists/thromboxane A synthetase inhibitors(such as picotamide), serotonin-2-receptor antagonists (such asketanserin), fibrinogen receptor antagonists, hypolipidemic agents, suchas HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, AZ4522, and itavastatin(Nissan/Kowa); microsomal triglyceride transport protein inhibitors(such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and5,760,246), antihypertensive agents such as angiotensin-convertingenzyme inhibitors (e.g., captopril, lisinopril or fosinopril);angiotensin-II receptor antagonists (e.g., irbesartan, losartan orvalsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat andgemopatrilat); β-blockers (such as propranolol, nadolol and carvedilol),PDE inhibitors in combination with aspirin, ifetroban, picotamide,ketanserin, or clopidogrel (Plavix®) and the like.

The compound of the present invention can also be used in combinationwith anti-arrhythmic agents such as for atrial fibrillation, forexample, amiodarone or dofetilide.

The compound of the present invention can also be used in combinationwith Cholesteryl ester transfer protein (CETP) inhibitors fordislipidemia and atherosclerosis, Niacin or niacin analogs fordislipidemia and atherosclerosis, Adenosine or adenosine analogs forvasodilation, Nitroglycerin or nitrates for vasodilation.

The compounds of the present invention can be used in combination withprothrombolytic agents, such as tissue plasminogen activator (natural orrecombinant), streptokinase, reteplase, activase, lanoteplase,urokinase, prourokinase, anisolated streptokinase plasminogen activatorcomplex (ASPAC), animal salivary gland plasminogen activators, and thelike. The compounds of the present invention may also be used incombination with β-adrenergic agonists such as albuterol, terbutaline,formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol;anticholinergics such as ipratropium bromide; anti-inflammatorycortiocosteroids such as beclomethasone, triamcinolone, budesonide,fluticasone, flunisolide or dexamethasone; and anti-inflammatory agentssuch as cromolyn, nedocromil, theophylline, zileuton, zafirlukast,monteleukast and pranleukast.

Suitable pharmaceutical agents that can be used in combination withcompounds of the present invention include antiretrovirals [see, e.g.,Turpin, Expert Rev Anti Infect Ther (2003) 1:97-128]. Some embodimentsof the present invention include methods of treatment of progressivemultifocal leukoencephalopathy as described herein comprisingadministering to an individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention in combination with at least one pharmaceutical agent selectedfrom the group consisting of: nucleoside reverse transcriptaseinhibitors (for example, Retrovir®, Epivir®, Combivir®, Videx®,Trizvir®, Zerit®, Ziagen®, Vired®, Emtricitabine, DAPD, and the like),non-nucleoside reverse transcriptase inhibitors (for example,Virammune®, Rescriptor®, Sustiva®, GW687, DPC083, TMC 125, Emivirine,Capravirine, BMS 561390, UC-781 and other oxathiin carboxyanilides,SJ-3366, Alkenyldiarylmethane (ADAM), Tivirapine, Calanolide A, HBY097,Loviride, HEPT Family Derivatives, TIBO Derivatives, and the like),protease inhibitors (for example, Fortovase®, Invirase®, Novir®,Crixivan®, Viracep®, Ageberase®, Kaletra®, Atazanavir, Tipranavir,DMP450, and the like), inhibitors of HIV-cell interaction (for example,soluble CD4, toxin-conjugated CD4, monoclonal antibodies to CD4 orgp120, PRO 542, dextran sulfate, Rersobene, FP-23199, Cyanovirin-N,Zintevir (T30177, AR177), L-chicoric acid and derivatives, and thelike), coreceptor inhibitors ligands (for example, R5, X4, modifiedligands (R5), modified ligands (X4), and the like), coreceptorinhibitors X4 (for example, T22, T134, ALX40-4C, AMD3100, bycyclamderivatives, and the like), coreceptor inhibitors R5 (for example,TAK-779, SCH-C(SCH-351125), SCH-D (SCH-350634), NSC 651016, ONOPharmaceutical, Merck, and the like), fusion inhibitors (for example,Fuzeon® (T-20, DP 178, enfuvritide) trimeris, T-1249, TMC125, and thelike), integrase inhibitors (for example, 5CITEP, L731,988, L708,906,L-870,812, S-1360, and the like), NCp7 nucleocapsid Zn finger inhibitors(for example, NOBA, DIBA, dithianes, PD-161374, pyridinioalkanoylthioesters (PATES), azodicarbonamide (ADA), cyclic 2,2 dithiobisbenzamide, and the like), RNase H inhibitors (for example, BBHN, CPHMPD-26388, and the like), Tat inhibitors (for example, dominant negativemutants, Ro24-7429, Ro5-3335, and the like), Rev inhibitors (forexample, dominant negative mutants, Leptomycin B, PKF050-638, and thelike), transcriptional inhibitors (for example, Temacrazine, K-12 andK-37, EM2487, and the like), inhibitors of HIV assembly/maturation (forexample, CAP-1 and CAP-2, and the like), and pharmaceutical agentsdirected to cellular anti-HIV targets (for example, LB6-B275 andHRM1275, Cdk9 inhibitors, and the like).

In a certain embodiment, a compound of the invention can be used inconjunction with highly active antiretroviral therapy (HAART). Whenantiretroviral drugs are used in combinations of three or four drugs,this treatment is called HAART [see, e.g., Portegies, et al., Eur. J.Neurol. (2004) 11:297-304].

In accordance with the present invention, the combination of a compoundof the present invention and pharmaceutical agent can be prepared bymixing the respective active components either all together orindependently with a pharmaceutically acceptable carrier, excipient,binder, diluent, etc. as described herein, and administering the mixtureor mixtures either orally or non-orally as a pharmaceuticalcomposition(s). When a compound or a mixture of compounds of Formula(Ia) are administered as a combination therapy with another activecompound each can be formulated as separate pharmaceutical compositionsgiven at the same time or at different times. Alternatively, in someembodiments, pharmaceutical compositions of the present inventioncomprise a compound or a mixture of compounds of Formula (Ia) and thepharmaceutical agent(s) as a single pharmaceutical composition.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the 5-HT_(2A) receptor in tissue samples,including human, and for identifying 5-HT_(2A) receptor ligands byinhibition binding of a radio-labeled compound. It is a further objectof this invention to develop novel 5-HT_(2A) receptor assays of whichcomprise such radio-labeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. An “isotopically” or “radio-labeled” compounds arethose which are identical to compounds disclosed herein, but for thefact that one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include, but are not limited to, ²H (also written as Dfor deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I,¹²⁵I, and ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro 5-HT_(2A) receptorlabeling and competition assays, compounds that incorporate ³H, ¹⁴C,⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (Ia) that has incorporated at least oneradionuclide; in some embodiments the radionuclide is selected from thegroup consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the more scarce radio-isotope ornonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]—This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol Synthetic methods for incorporatingactivity levels of ¹²⁵I into target molecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)4]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled 5-HT_(2A) receptor compound of Formula (Ia) can be usedin a screening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (Ia)” to the 5-HT_(2A) receptor. Accordingly, theability of a test compound to compete with the “radio-labeled compoundof Formula (Ia)” for the binding to the 5-HT_(2A) receptor directlycorrelates to its binding affinity.

The labeled compounds of the present invention bind to the 5-HT_(2A)receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM, and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1 Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIGS. 1 through 8 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds of the invention and their synthesis are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to CS Chem Draw UltraVersion 7.0.1 or AutoNom 2000. In certain instances common names areused and it is understood that these common names would be recognized bythose skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Varian Mercury Vx-400 equipped with a 4 nucleus autoswitchable probe and z-gradient or a Bruker Avance-400 or 500 MHzequipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse)and z-gradient. Chemical shifts are given in parts per million (ppm)with the residual solvent signal used as reference. NMR abbreviationsare used as follows: s=singlet, d=doublet, dd=doublet of doublet,ddd=doublet of doublet of doublet, dt=doublet of triplet, t=triplet,q=quartet, m=multiplet, br=broad. Microwave irradiations were carriedout using the Emrys Synthesizer (Personal Chemistry). Thin-layerchromatography (TLC) was performed on silica gel 60 F₂₅₄ (Merck),preparatory thin-layer chromatography (prep TLC) was preformed on PK6Fsilica gel 60 A 1 mm plates (Whatman), and column chromatography wascarried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm(Merck). Evaporation was done under reduced pressure on a Buchi rotaryevaporator. Celite 545® was used during palladium filtrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller:SCL-10A VP, Shimadzu Inc.

UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215 Liquid Handler,Gilson Inc; Mass spectrometer: API 150EX with Turbo Ion Spray source,AB/MDS Sciex

Software: Masschrom 1.5.2. Example 1 Preparation of Compounds Example1.1 Preparation of 3-chloro-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 334) Step A: Preparation of{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid tert-butyl ester

A heterogenous solution of4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenol (1.9 g, 8.5 mmol),Boc-amino-ethylbromide (4.2 g, 2.2 eq), and K₂CO₃ (2.3 g, 2.0 eq.) inacetone (80 mL) was refluxed for 35 h. The reaction was filtered andconcentrated. The crude product was dissolved in DCM (30 mL), washedwith 1N—NaOH to remove unreacted starting material and with H₂O, dried,and concentrated. The residue was purified by column chromatography(silica gel, hexane:EtOAc:MeOH=5:1:0 to 2:1:0.1) to afford 2.2 g (71%){2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid tert-butyl ester. LCMS m/z (%)=367.2 (M+H ³⁵Cl, 100), 369.2 (M+H³⁷Cl, 30).

Step B: Preparation of 3-chloro-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 334)

A solution of{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid tert-butyl ester (15 mg, 40 μmol), 3-chlorothiophene-2-carbonylchloride (12 mg, 1.5 eq.), DIEA (13 mg, 2.5 eq.) in DCM (1 mL) wasstirred overnight. MeOH (˜0.1 mL) was added into the reaction to quenchthe excess acid chloride. After stirring for 30 min, the reaction wastreated with TFA (˜0.2 mL) and heated to ˜90° C. for 1 h. The reactionwas neutralized with sat-NaHCO₃ and purified by prep-HPLC: Waters YMCODS-A™ C18 column (5μ, 4.6×50 mm), 5% v/v CH₃CN (containing 0.05% v/vTFA) in H₂O (containing 0.05% v/v TFA) gradient to 60% v/v CH₃CN in H₂O,20 mL/min 3-Chloro-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (15 mg, 89%) was isolated as a white powder. LCMS m/z(%)=411.0 (M+H ³⁵Cl, 100), 413.0 (M+H ³⁷Cl, 68). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.3 (s, 1H), 7.95-7.82 (m, 5H), 7.65 (s, 1H), 7.63 (d,J=2.4 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 4.20 (m,2H), 3.66 (s, 3H), 3.16 (m, 2H).

Example 1.2 Preparation of 5-methyl-2-trifluoromethyl-furan-3-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 47)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=443.2 (M+H ³⁵Cl, 100), 445.2 (M+H³⁷Cl, 31).

Example 1.3 Preparation of 5-methyl-isoxazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 57)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=376.2 (M+H ³⁵Cl, 100), 378.2 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.8 (s, 1H), 7.94 (dd, J=2.4and 9.1 Hz, 1H), 7.86 (bs, 3H), 7.74 (d, J=2.4 Hz, 1H), 7.65 (s, 1H),7.28 (d, J=9.1 Hz, 1H), 6.66 (s, 1H), 4.20 (m, 2H), 3.67 (s, 3H), 3.15(m, 2H), 2.50 (s, 3H).

Example 1.4 Preparation of 2,2-difluoro-benzo[1,3]dioxole-4-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 67)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=451.0 (M+H ³⁵Cl, 100), 453.0 (M+H³⁷Cl, 31).

Example 1.5 Preparation of 4-bromo-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 77)

The title compound was prepared in a similar manner as described inExample 1.1, Step B LCMS m/z (%)=455.3 (M+H ³⁵Cl⁷⁹Br, 74), 457.3 (M+H³⁷Cl⁷⁹Br, 100), 459.3 (M+H ³⁷Cl⁸¹Br, 24).

Example 1.6 Preparation of3-chloro-6-fluoro-benzo[b]thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 82)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=479.1 (M+H ³⁵Cl, 100), 481.1 (M+H³⁷Cl, 68). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.6 (s, 1H), 8.13 (dd, J=2.4and 9.1 Hz, 1H), 8.00-7.83 (m, 6H), 7.66 (s, 1H), 7.52 (dt, J=2.2 and9.1 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 4.21 (m, 2H), 3.68 (s, 3H), 3.16(m, 2H).

Example 1.7 Preparation of 3-methyl-benzofuran-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 87)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=424.9 (M+H ³⁵Cl, 100), 426.9 (M+H³⁷Cl, 31).

Example 1.8 Preparation of cyclopentanecarboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 274)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=363.1 (M+H ³⁵Cl, 100), 365.1 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.95 (s, 1H), 7.87 (bs, 3H),7.74 (dd, J=2.4 and 9.1 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=2.4 Hz, 1H),7.20 (d, J=9.0 Hz, 1H), 4.15 (m, 2H), 3.64 (s, 3H), 3.13 (m, 2H), 2.74(m, 1H), 1.89-1.51 (m, 8H).

Example 1.9 Preparation of5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 283)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=431.3 (M+H ³⁵Cl, 100), 433.3 (M+H³⁷Cl, 31).

Example 1.10 Preparation of 2,5-dichloro-thiophene-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 63)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=445.2 (M+H ³⁵Cl, 100), 447.2 (M+H³⁷Cl, 99), 449.2 (M+H ³⁷Cl, 35). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.4 (s,1H), 7.86 (m, 4H), 7.65 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.51 (s, 1H),7.28 (d, J=9.0 Hz, 1H), 4.19 (m, 2H), 3.66 (s, 3H), 3.16 (m, 2H).

Example 1.11 Preparation of 3,5-dimethyl-isoxazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 78)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=390.4 (M+H ³⁵Cl, 100), 392.4 (M+H³⁷Cl, 31).

Example 1.12 Preparation of1-phenyl-5-trifluoromethyl-1H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 93)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=505.3 (M+H ³⁵Cl, 100), 507.3 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.6 (s, 1H), 8.31 (s, 1H), 7.88(m, 4H), 7.66 (s, 1H), 7.62 (m, 4H), 7.53 (m, 2H), 7.29 (d, J=9.1 Hz,1H), 4.20 (m, 2H), 3.67 (s, 3H), 3.16 (m, 2H).

Example 1.13 Preparation of 2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 6)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=451.0 (M+H ³⁵Cl, 100), 453.0 (M+H³⁷Cl, 31).

Example 1.14 Preparation of5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 12)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=539.4 (M+H ³⁵Cl, 100), 541.4 (M+H³⁷Cl, 65).

Example 1.15 Preparation of1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 18)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=539.4 (M+H ³⁵Cl, 100), 541.4 (M+H³⁷Cl, 65). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.6 (s, 1H), 8.34 (s, 1H), 7.87(m, 4H), 7.70-7.58 (m, 6H), 7.29 (d, J=9.1 Hz, 1H), 4.20 (m, 2H), 3.67(s, 3H), 3.16 (m, 2H).

Example 1.16 Preparation of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 24)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=389.1 (M+H ³⁵Cl, 100), 391.1 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.1 (s, 1H), 7.96 (dd, J=2.5and 9.1 Hz, 1H), 7.86 (bs, 3H), 7.78 (d, J=2.4 Hz, 1H), 7.64 (s, 1H),7.23 (d, J=9.1 Hz, 1H), 6.53 (s, 1H), 4.18 (m, 2H), 3.83 (s, 3H), 3.67(s, 3H), 3.15 (m, 2H), 2.30 (s, 3H).

Example 1.17 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamidetrifluoroacetate (Compound 30)

A solution of 4-methoxy-3-methylbenzoic acid (10 mg, 59 μmol), HATU (23mg, 1.1 eq), and Et₃N (11 mg, 1.5 eq.) in DCM (1 mL) was stirred 20 minat 40° C.{2-[4-Amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid tert-butyl ester (18 mg, 50 μmol) was added into the acid-HATUsolution, and the reaction was stirred overnight at 40 C. The reactionwas treated with TFA (˜0.2 mL) and heated to ˜90° C. for 1 h. Thereaction was filtered through a strong cation exchange resin to removeimpurity, TFA, and tetramethyl urea, and purified by prep-HPLC: WatersYMC ODS-A™ C18 column (5μ, 4.6×50 mm), 5% v/v

CH₃CN (containing 0.05% v/v TFA) in H₂O (containing 0.05% v/v TFA)gradient to 60% v/v CH₃CN in H₂O, 20 mL/min.N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamidetrifluoroacetate (14 mg, 69%) was obtained as a white powder. LCMS m/z(%)=415.3 (M+H ³⁵Cl, 100), 417.3 (M+H ³⁷Cl, 31). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.1 (s, 1H), 7.93 (dd, J=2.5 and 8.8 Hz, 1H), 7.91-7.82 (m,4H), 7.79 (bs, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.65 (s, 1H), 7.27 (d, J=9.0Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.19 (m, 2H), 3.86 (s, 3H), 3.67 (s,3H), 3.16 (m, 2H), 2.21 (s, 3H).

Example 1.18 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-4-methoxy-benzamidetrifluoroacetate (Compound 198)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=479.2 (M+H ³⁵Cl ⁷⁹Br, 77), 481.2 (M+H³⁷Cl⁷⁹Br, 100), 483.2 (M+H ³⁷Cl⁸¹Br, 25).

Example 1.19 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methoxy-benzamidetrifluoroacetate (Compound 212)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=419.2 (M+H ³⁵Cl, 100), 421.2 (M+H ³⁷Cl, 31).

Example 1.20 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamidetrifluoroacetate (Compound 227)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=419.0 (M+H ³⁵Cl, 100), 421.0 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.2 (s, 1H), 7.94-7.85 (m, 4H), 7.68-7.61(m, 3H), 7.27 (d, J=9.0 Hz, 1H), 6.97 (dd, J=2.2 and 12.6 Hz, 1H), 6.90(dd, J=2.4 and 8.8 Hz, 1H), 4.19 (m, 2H), 3.83 (s, 3H), 3.66 (s, 3H),3.15 (m, 2H).

Example 1.21 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamidetrifluoroacetate (Compound 242)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=437.1 (M+H ³⁵Cl, 100), 439.1 (M+H ³⁷Cl, 31).

Example 1.22 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-trifluoromethyl-benzamidetrifluoroacetate (Compound 258)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=469.5 (M+H ³⁵Cl, 100), 471.5 (M+H ³⁷Cl, 31).

Example 1.23 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-2-methyl-benzamidetrifluoroacetate (Compound 98)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=415.3 (M+H ³⁵Cl, 100), 417.3 (M+H ³⁷Cl, 31).

Example 1.24 Preparation ofN-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methoxy-benzamidetrifluoroacetate (Compound 116)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=419.0 (M+H ³⁵Cl, 100), 421.0 (M+H ³⁷Cl, 31).

Example 1.25 Preparation ofN-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-3-methoxy-benzamidetrifluoroacetate (Compound 128)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=419.0 (M+H ³⁵Cl, 100), 421.0 (M+H ³⁷Cl, 31).

Example 1.26 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-5-methoxy-2-(2,2,2-trifluoro-ethoxy)-benzamidetrifluoroacetate (Compound 186)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=499.2 (M+H ³⁵Cl, 100), 501.2 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.2 (s, 1H), 7.93-7.82 (m, 4H), 7.65 (s,1H), 7.63 (d, J=2.4 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.23 (d, J=8.8 Hz,1H), 7.14 (d, J=2.8 Hz, 1H), 7.09 (dd, J=2.8 and 8.8 Hz, 1H), 4.78 (q,J=9.0 Hz, 2H), 4.19 (m, 2H), 3.77 (s, 3H), 3.67 (s, 3H), 3.15 (m, 2H).

Example 1.27 Preparation of benzo[1,3]dioxole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 33)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=415.2 (M+H ³⁵Cl, 100), 417.2 (M+H ³⁷Cl, 31).

Example 1.28 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-thiophen-2-yl-benzamidetrifluoroacetate (Compound 35)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=453.1 (M+H ³⁵Cl, 100), 455.1 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.3 (s, 1H), 8.01 (d, J=11.0 Hz, 2H), 7.96(dd, J=2.6 and 8.8 Hz, 1H), 7.90-7.81 (m, 5H), 7.73 (d, J=2.8 Hz, 1H),7.69 (d, J=2.8 Hz, 1H), 7.66 (m, 2H), 7.29 (d, J=9.2 Hz, 1H), 7.19 (m,1H), 4.21 (m, 2H), 3.68 (s, 3H), 3.16 (m, 2H).

Example 1.29 Preparation of adamantane-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate. (Compound 37)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=429.0 (M+H ³⁵Cl, 100), 431.0 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.20 (s, 1H), 7.85 (m, 4H), 7.63(s, 1H), 7.60 (d, J=2.8 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 4.16 (m, 2H),3.64 (s, 3H), 3.13 (bs, 2H), 2.00 (bs, 3H), 1.89 (m, 6H), 1.70 (bs, 6H).

Example 1.30 Preparation of pyridine-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 39)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=371.9 (M+H ³⁵Cl, 100), 373.9 (M+H³⁷Cl, 31).

Example 1.31 Preparation of pyridine-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 43)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=371.8 (M+H ³⁵Cl, 100), 373.8 (M+H³⁷Cl, 31).

Example 1.32 Preparation of pyridine-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 51)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=371.8 (M+H ³⁵Cl, 100), 373.8 (M+H³⁷Cl, 31).

Example 1.33 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-isonicotinamidetrifluoroacetate (Compound 61)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=390.1 (M+H ³⁵Cl, 100), 392.1 (M+H³⁷Cl, 31).

Example 1.34 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-5-bromo-nicotinamidetrifluoroacetate (Compound 71)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=449.8 (M+H ³⁵Cl⁷⁹Br, 74), 451.8 (M+H³⁷Cl⁷⁹Br, 100), 453.8 (M+H ³⁷Cl⁸¹Br, 24).

Example 1.35 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-bromo-benzamidetrifluoroacetate (Compound 91)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=448.9 (M+H ³⁵Cl⁷⁹Br, 74), 450.9 (M+H³⁷Cl⁷⁹Br, 100), 452.9 (M+H ³⁷Cl⁸¹Br, 24).

Example 1.36 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-dimethylamino-benzamidetrifluoroacetate (Compound 5)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=414.3 (M+H ³⁵Cl, 100), 416.3 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.2 (s, 1H), 7.96-7.84 (m, 4H),7.71 (d, J=2.8 Hz, 1H), 7.65 (s, 1H), 7.34-7.21 (m, 4H), 6.94 (d, J=8.4Hz, 1H), 4.20 (m, 2H), 3.67 (s, 3H), 3.15 (m, 2H), 2.96 (s, 6H).

Example 1.37 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-dimethylamino-benzamidetrifluoroacetate (Compound 11)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=414.2 (M+H ³⁵Cl, 100), 416.2 (M+H³⁷Cl, 31).

Example 1.38 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-cyano-benzamidetrifluoroacetate (Compound 17)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=395.9 (M+H ³⁵Cl, 100), 397.9 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.6 (s, 1H), 8.12-7.80 (m, 8H),7.72 (d, J=2.8 Hz, 1H), 7.66 (s, 1H), 7.30 (d, J=9.2 Hz, 1H), 4.21 (m,2H), 3.67 (s, 3H), 3.16 (m, 2H).

Example 1.39 Preparation of quinoline-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 23)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=422.0 (M+H ³⁵Cl, 100), 424.0 (M+H³⁷Cl, 31).

Example 1.40 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-ethyl-benzamidetrifluoroacetate (Compound 31)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=399.0 (M+H ³⁵Cl, 100), 401.0 (M+H³⁷Cl, 31).

Example 1.41 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-phenoxy-nicotinamidetrifluoroacetate (Compound 205)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=464.1 (M+H ³⁵Cl, 100), 466.1 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.6 (s, 1H), 8.23 (dd, J=2.0and 4.8 Hz, 1H), 8.10 (dd, J=2.0 and 7.6 Hz, 1H), 7.90-7.83 (m, 4H),7.69 (d, J=2.5 Hz, 1H), 7.65 (s, 1H), 7.42 (t, J=7.8 Hz, 2H), 7.30-7.18(m, 5H), 4.19 (m, 2H), 3.65 (s, 3H), 3.15 (m, 2H).

Example 1.42 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methyl-benzamidetrifluoroacetate (Compound 292)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=403.1 (M+H ³⁵Cl, 100), 405.1 (M+H³⁷Cl, 31).

Example 1.43 Preparation ofN-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-3-fluoro-benzamidetrifluoroacetate (Compound 304)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=422.8 (M+H ³⁵Cl, 100), 424.8 (M+H³⁵Cl³⁷Cl, 64), 426.8 (M+H ³⁷Cl, 23).

Example 1.44 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3,4-difluoro-benzamidetrifluoroacetate (Compound 313)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=407.0 (M+H ³⁵Cl, 100), 409.0 (M+H³⁷Cl, 31).

Example 1.45 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3,5-difluoro-benzamidetrifluoroacetate (Compound 319)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=407.1 (M+H ³⁵Cl, 100), 409.1 (M+H³⁷Cl, 31).

Example 1.46 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-trifluoromethyl-benzamidetrifluoroacetate (Compound 197)

The title compound was prepared in a similar manner as described inExample 1.1, Step B. LCMS m/z (%)=457.1 (M+H ³⁵Cl, 100), 459.1 (M+H³⁷Cl, 31). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.6 (s, 1H), 8.35 (m, 2H),7.95-7.82 (m, 4H), 7.72 (m, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.66 (s, 1H),7.39 (d, J=9.2 Hz, 1H), 4.21 (m, 2H), 3.67 (s, 3H), 3.16 (m, 2H).

Example 1.47 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-4-methyl-benzamidetrifluoroacetate (Compound 206)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=415.4 (M+H ³⁵Cl, 100), 417.4 (M+H ³⁷Cl, 31).

Example 1.48 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-2-methyl-benzamidetrifluoroacetate (Compound 216)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=415.5 (M+H ³⁵Cl, 100), 417.5 (M+H ³⁷Cl, 31).

Example 1.49 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3,5-dimethyl-benzamidetrifluoroacetate (Compound 226)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=429.3 (M+H ³⁵Cl, 100), 431.3 (M+H ³⁷Cl, 31).

Example 1.50 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-methoxy-benzamidetrifluoroacetate (Compound 236)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=435.3 (M+H ³⁵Cl, 100), 437.3 (M+H ³⁷Cl, 64).

Example 1.51 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-bromo-5-methoxy-benzamidetrifluoroacetate (Compound 246)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=479.5 (M+H³⁵Cl⁷⁹Br, 74), 481.5 (M+H ³⁷Cl⁷⁹Br,100), 483.5 (M+H ³⁷Cl⁸¹Br, 24). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.5 (s,1H), 7.94-7.83 (m, 4H), 7.65 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.14 (d, J=2.8 Hz, 1H), 7.06 (dd,J=2.8 and 8.8 Hz, 1H), 4.21 (m, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 3.16(m, 2H).

Example 1.52 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-6-pyrrolidin-1-yl-nicotinamidetrifluoroacetate (Compound 263)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=441.3 (M+H ³⁵Cl, 100), 443.3 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.2 (s, 1H), 8.66 (s, 1H), 8.14 (dd, J=2.0and 9.1 Hz, 1H), 7.94-7.86 (m, 4H), 7.68 (d, J=2.8 Hz, 1H), 7.65 (s,1H), 7.27 (d, J=9.0 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.19 (m, 2H), 3.67(s, 3H), 3.50 (m, 4H), 3.15 (m, 2H), 1.99 (m, 4H).

Example 1.53 Preparation of 1H-indole-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 103)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=410.4 (M+H ³⁵Cl, 100), 412.4 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 11.7 (s, 1H), 10.3 (s, 1H), 7.98 (dd, J=3.0and 8.8 Hz, 1H), 7.89 (bs, 3H), 7.77 (d, J=2.8 Hz, 1H), 7.68 (d, J=7.4Hz, 1H), 7.67 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.40 (bs, 1H), 7.30 (d,J=9.1 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 4.21 (m,2H), 3.69 (s, 3H), 3.16 (m, 2H).

Example 1.54 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 127)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=506.2 (M+H ³⁵Cl, 100), 508.2 (M+H ³⁷Cl, 31).

Example 1.55 Preparation of 2,2-difluoro-cyclopropanecarboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 150)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=371.1 (M+H ³⁵Cl, 100), 373.1 (M+H ³⁷Cl, 31).

Example 1.56 Preparation of tetrahydro-furan-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 174)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=365.1 (M+H ³⁵Cl, 100), 367.1 (M+H ³⁷Cl, 31).

Example 1.57 Preparation of 4-trifluoromethyl-cyclohexanecarboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 303)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=445.3 (M+H ³⁵Cl, 100), 447.3 (M+H ³⁷Cl, 31).

Example 1.58 Preparation of thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 315)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=377.0 (M+H ³⁵Cl, 100), 379.0 (M+H ³⁷Cl, 31).

Example 1.59 Preparation of 3-ethoxy-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 195)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=421.1 (M+H ³⁵Cl, 100), 423.1 (M+H ³⁷Cl, 31).

Example 1.60 Preparation of 1-methyl-1H-pyrrole-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 209)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=374.0 (M+H ³⁵Cl, 100), 376.0 (M+H ³⁷Cl, 31).

Example 1.61 Preparation of 3-methyl-isoxazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 224)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=376.0 (M+H ³⁵Cl, 100), 378.0 (M+H ³⁷Cl, 31).

Example 1.62 Preparation of 5-methyl-isoxazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 244)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=376.2 (M+H ³⁵Cl, 100), 378.2 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 11.5 (s, 1H), 7.83 (bs, 4H), 7.62 (s, 1H),7.59 (dd, J=2.4 and 9.1 Hz, 1H), 7.50 (d, J=2.8 Hz, 1H), 7.18 (d, J=9.1Hz, 1H), 4.14 (m, 2H), 3.65 (s, 3H), 3.12 (m, 2H), 2.10 (s, 3H).

Example 1.63 Preparation of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 267)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=403.2 (M+H ³⁵Cl, 100), 405.2 (M+H ³⁷Cl, 31).

Example 1.64 Preparation of 1-methyl-1H-imidazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 107)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=375.5 (M+H ³⁵Cl, 100), 377.5 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.1 (s, 1H), 8.00-7.74 (m, 7H), 7.64 (s,1H), 7.24 (d, J=9.1 Hz, 1H), 4.18 (m, 2H), 3.75 (s, 3H), 3.67 (s, 3H),3.14 (m, 2H).

Example 1.65 Preparation of thiazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 119)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=378.0 (M+H ³⁵Cl, 100), 380.0 (M+H ³⁷Cl, 31).

Example 1.66 Preparation of 4-methyl-thiazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 137)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=391.9 (M+H ³⁵Cl, 100), 393.9 (M+H ³⁷Cl, 31).

Example 1.67 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,2-dimethyl-propionamidetrifluoroacetate (Compound 171)

The title compound was prepared in a similar manner as described inExample 1.1, Step B LCMS m/z (%)=351.3 (M+H ³⁵Cl, 100), 353.3 (M+H ³⁷Cl,31).

Example 1.68 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4,5-trifluoro-3-methoxy-benzamidetrifluoroacetate (Compound 189)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=455.3 (M+H ³⁵Cl, 100), 457.3 (M+H ³⁷Cl, 31).

Example 1.69 Preparation of 4,4-difluoro-cyclohexanecarboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 332)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=413.3 (M+H ³⁵Cl, 100), 415.3 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 12.3 (bs, 1H), 10.0 (s, 1H), 7.90 (bs, 2H),7.74 (dd, J=2.6 and 9.1 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=2.8 Hz, 1H),7.21 (d, J=9.1 Hz, 1H), 4.16 (m, 2H), 3.63 (s, 3H), 3.13 (bs, 2H), 2.42(m, 1H), 2.14-1.60 (m, 8H).

Example 1.70 Preparation of 3-methyl-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 49)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=391.0 (M+H ³⁵Cl, 100), 393.0 (M+H ³⁷Cl, 64).

Example 1.71 Preparation of 5-methyl-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 64)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=391.0 (M+H ³⁵Cl, 100), 393.0 (M+H ³⁷Cl, 64).

Example 1.72 Preparation of 5-chloro-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 74)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=411.1 (M+H ³⁵Cl, 100), 413.1 (M+H ³⁷Cl, 64).¹H NMR (400 MHz, DMSO-d₆) δ: 10.3 (s, 1H), 7.90-7.81 (m, 5H), 7.65 (s,1H), 7.61 (m, 1H), 7.28 (m, 1H), 7.24 (d, J=4.0 Hz, 1H), 4.23 (m, 2H),3.66 (s, 3H), 3.15 (m, 2H).

Example 1.73 Preparation of 4,5-dichloro-isothiazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 84)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=446.1 (M+H ³⁵Cl, 99), 448.1 (M+H ³⁷Cl, 100),450.1 (M+H ³⁷Cl, 36). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.9 (s, 1H),7.90-7.82 (m, 4H), 7.71 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.29 (d, J=9.0Hz, 1H), 4.21 (m, 2H), 3.67 (s, 3H), 3.16 (m, 2H).

Example 1.74 Preparation of5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 94)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=477.3 (M+H ³⁵Cl, 100), 479.3 (M+H ³⁷Cl, 63).

Example 1.75 Preparation of 5-isopropyl-2H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 278)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=403.1 (M+H ³⁵Cl, 100), 405.1 (M+H ³⁷Cl, 31).

Example 1.76 Preparation of 5-methyl-1H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 284)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=375.3 (M+H ³⁵Cl, 100), 377.3 (M+H ³⁷Cl, 31).

Example 1.77 Preparation of 4-chloro-1-ethyl-1H-pyrazole-3-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 296)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=422.9 (M+H ³⁵Cl, 100), 424.9 (M+H ³⁷Cl, 64).

Example 1.78 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-methylsulfanyl-nicotinamidetrifluoroacetate (Compound 305)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=417.7 (M+H ³⁵Cl, 100), 419.7 (M+H ³⁷Cl, 31).

Example 1.79 Preparation of benzo[c]isoxazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 317)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=411.9 (M+H ³⁵Cl, 100), 413.9 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 11.2 (s, 1H), 8.01 (m, 2H), 7.95-7.75 (m,5H), 7.67 (s, 1H), 7.54 (m, 1H), 7.33 (m, 2H), 4.23 (m, 2H), 3.69 (s,3H), 3.18 (m, 2H).

Example 1.80 Preparation of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 203)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=429.2 (M+H ³⁵Cl, 100), 431.2 (M+H ³⁷Cl, 31).

Example 1.81 Preparation of4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 223)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=442.4 (M+H ³⁵Cl, 100), 444.4 (M+H ³⁷Cl, 31).

Example 1.82 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-6-morpholin-4-yl-nicotinamidetrifluoroacetate (Compound 140)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=457.3 (M+H ³⁵Cl, 100), 459.3 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.1 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.10(dd, J=2.4 and 9.1 Hz, 1H), 7.91 (dd, J=2.8 and 9.1 Hz, 1H), 7.86 (bs,3H), 7.69 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.93(d, J=9.1 Hz, 1H), 4.18 (m, 2H), 3.69 (m, 4H), 3.67 (s, 3H), 3.60 (m,4H), 3.15 (m, 2H).

Example 1.83 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(1,1,2,2-tetrafluoro-ethoxy)-benzamidetrifluoroacetate (Compound 46)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=487.4 (M+H ³⁵Cl, 100), 489.4 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.4 (s, 1H), 8.05 (d, J=8.8 Hz, 2H),7.95-7.86 (m, 4H), 7.71 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.45 (d, J=8.8Hz, 2H), 7.29 (d, J=9.1 Hz, 1H), 6.86 (tt, J=3.0 and 51 Hz, 1H), 4.20(m, 2H), 3.67 (s, 3H), 3.15 (m, 2H).

Example 1.84 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-ethoxy-benzamidetrifluoroacetate (Compound 56)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=415.5 (M+H ³⁵Cl, 100), 417.5 (M+H ³⁷Cl, 31).

Example 1.85 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-isopropoxy-benzamidetrifluoroacetate (Compound 66)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=429.5 (M+H ³⁵Cl, 100), 431.5 (M+H ³⁷Cl, 31).

Example 1.86 Preparation of 2-bromo-4-methyl-thiazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 86)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=470.1 (M+H ³⁵Cl⁷⁹Br, 74), 472.1 (M+H³⁷Cl⁷⁹Br, 100), 474.1 (M+H ³⁷Cl⁸¹Br, 24).

Example 1.87 Preparation of 2,4-dimethyl-thiazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 3)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=406.2 (M+H ³⁵Cl, 100), 408.2 (M+H ³⁷Cl, 31).

Example 1.88 Preparation of 4,5-dimethyl-furan-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 9)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=389.1 (M+H ³⁵Cl, 100), 391.1 (M+H ³⁷Cl, 31).

Example 1.89 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-5-methyl-nicotinamidetrifluoroacetate (Compound 15)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=386.4 (M+H ³⁵Cl, 100), 388.4 (M+H ³⁷Cl, 31).

Example 1.90 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyclopentyloxy-4-methoxy-benzamidetrifluoroacetate (Compound 21)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=485.3 (M+H ³⁵Cl, 100), 487.3 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.1 (s, 1H), 7.97-7.89 (m, 4H), 7.70 (d,J=2.4 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J=2.0 and 8.8 Hz, 1H), 7.50 (d,J=2.4 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.09 (d, J=9.1 Hz, 1H), 4.87 (m,1H), 4.20 (m, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 3.16 (m, 2H), 1.89 (m,2H), 1.73 (m, 4H), 1.59 (m, 2H).

Example 1.91 Preparation of 6-oxo-1,6-dihydro-pyridazine-3-carboxylicacid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 29)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=389.3 (M+H ³⁵Cl, 100), 391.3 (M+H ³⁷Cl, 31).

Example 1.92 Preparation of 5-methyl-pyrazine-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 201)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=387.3 (M+H ³⁵Cl, 100), 389.3 (M+H ³⁷Cl, 31).

Example 1.93 Preparation of cinnoline-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 289)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=423.1 (M+H ³⁵Cl, 100), 425.1 (M+H ³⁷Cl, 31).

Example 1.94 Preparation of 6-oxo-6H-pyran-3-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 301)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=389.2 (M+H ³⁵Cl, 100), 391.2 (M+H ³⁷Cl, 31).

Example 1.95 Preparation of 1H-benzotriazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 310)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=412.1 (M+H ³⁵Cl, 100), 414.1 (M+H ³⁷Cl, 31).

Example 1.96 Preparation ofN-[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-benzamidetrifluoroacetate (Compound 316)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=518.4 (M+H ³⁵Cl, 100), 520.4 (M+H ³⁷Cl, 31).¹H NMR (400 MHz, DMSO-d₆) δ: 10.3 (s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.88(bs, 4H), 7.72 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J=8.8 Hz, 2H),7.28 (d, J=9.1 Hz, 1H), 4.19 (m, 2H), 3.86 (bs, 2H), 3.67 (s, 3H), 3.18(m, 6H), 2.98 (m, 4H).

Example 1.97 Preparation of1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 192)

The title compound was prepared in a similar manner as described inExample 1.17. LCMS m/z (%)=443.1 (M+H ³⁵Cl, 100), 445.1 (M+H ³⁷Cl, 31).

Example 2 Preparation of Compounds Example 2.1 Preparation ofIsoxazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound106) Step A: Preparation of the intermediate tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate

4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (2 g, 10.6 mmol) wasdissolved in acetone (100 mL). Tert-butyl 2-bromoethylcarbamate (4.74 g,21.2 mmol) and potassium carbonate (2.92 g, 21.2 mmol) were then addedto the solution. The reaction was refluxed for 15 hours at 60° C. Afterthe reaction was completed, the reaction mixture was filtered,concentrated, and dissolved in CH₂Cl₂. The unreacted4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol was removed from the productthrough extraction with 1N NaOH. The product was purified by columnchromatography (40% EtOAc/60% Hexanes) to yield tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (1.56 g,4.70 mmol, 44.4%) as a white solid. LCMS m/z (%)=333 (M+H). ¹H NMR (400MHz, CDCl₃) δ ppm 1.42 (s, 9H), 3.33 (q, J=5.31 Hz, 2H), 3.55 (s, 2H),3.74 (s, 3H), 3.90 (t, J=5.05 Hz, 2H), 4.63 (br. s., 1H), 6.22 (d,J=1.77 Hz, 1H), 6.61 (d, J=3.03 Hz, 1H), 6.73 (dd, J=8.84, 2.78 Hz, 1H),6.84 (d, J=8.84 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H).

Step B: Preparation of Isoxazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (Compound 106)

To a solution of tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy), ethylcarbamate (20 mg,60 μmol) in CH₂Cl₂ (0.5 mL) was added isoxazole-5-carbonyl chloride (12mg, 90 μmol) and Et3N (20 μl, 144 μmol). The reaction mixture wasstirred for 4-5 hours at room temperature. Then, TFA (1 mL) was added tothe solution and heated for one hour at 90° C. in order to remove theBoc-protecting group from the amine. The solvent was evaporated, theresulting oil was dissolved in DMSO (1 mL) and purified by Prep LC/MS toyield isoxazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (12.2 mg,0.037 mmol, 60.6%) as a white solid. LCMS m/z (%)=328 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.17 (s, 2H), 3.72 (s, 3H), 4.20 (t, J=5.43 Hz, 2H),6.38 (d, J=1.77 Hz, 1H), 7.25 (d, J=1.77 Hz, 1H), 7.27 (s, 1H), 7.50 (d,J=1.77 Hz, 1H), 7.71 (d, J=2.53 Hz, 1H), 7.87 (br. s., 3H), 7.87 (dd,J=8.97, 2.65 Hz, 1H), 8.84 (d, J=1.77 Hz, 1H), 10.82 (s, 1H).

Example 2.2 Preparation of Benzo[1,3]dioxole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound121)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=381 (M+H). ¹HNMR (400 MHz, MeOH-d₄) δ ppm 3.28-3.31 (m, 2H), 3.80 (s, 3H), 4.26 (t,J=5.18 Hz, 2H), 6.08 (s, 2H), 6.41 (d, J=2.02 Hz, 1H), 6.96 (d, J=8.34Hz, 1H), 7.24 (d, J=9.09 Hz, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.53-7.59 (m,2H), 7.64 (t, J=2.78 Hz, 1H), 7.77-7.86 (m, 1H), 10.06 (s, 1H).

Example 2.3 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl))-phenyl]-4-bromo-3-methyl-benzamide(Compound 129)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=429 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 3.17 (q, J=5.56 Hz, 2H), 3.71(s, 3H), 4.18 (t, J=5.56 Hz, 2H), 6.36 (d, J=1.77 Hz, 1H), 7.24 (d,J=8.84 Hz, 1H), 7.49 (d, J=1.77 Hz, 1H), 7.68-7.72 (m, 2H), 7.77 (d,J=8.34 Hz, 1H), 7.89 (br. s., 3H), 7.86 (dd, J=8.97, 2.65 Hz, 1H), 7.93(d, J=2.02 Hz, 1H), 10.33 (s, 1H).

Example 2.4 Preparation of Naphthalene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound152)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=387 (M+H). H NMR(400 MHz, DMSO-d₆) δ ppm 3.18 (q, J=5.31 Hz, 2H), 3.74 (s, 3H), 4.20 (t,J=5.43 Hz, 2H), 6.39 (d, J=1.77 Hz, 1H), 7.27 (d, J=9.09 Hz, 1H), 7.51(d, J=1.77 Hz, 1H), 7.59-7.70 (m, 2H), 7.78 (d, J=2.78 Hz, 1H), 7.89(bs, 3H), 7.94 (dd, J=9.09, 2.78 Hz, 1H), 8.00-8.12 (m, 4H), 8.58 (s,1H), 10.49 (s, 1H).

Example 2.5 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-fluoro-benzamide(Compound 302)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=389 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.17 (q, J=5.56 Hz, 2H), 3.71 (s, 3H), 4.19(t, J=5.56 Hz, 2H), 6.36 (d, J=1.77 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H),7.49 (d, J=1.77 Hz, 1H), 7.61 (t, J=8.97 Hz, 1H), 7.71 (d, J=2.78 Hz,1H), 7.85 (dd, J=8.97, 2.65 Hz, 1H), 8.00 (br. s., 3H), 7.96-8.03 (m,1H), 8.20 (dd, J=7.07, 2.27 Hz, 1H), 10.41 (s, 1H).

Example 2.6 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-trifluoromethyl-benzamide(Compound 190)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=423 (M+H). ¹HNMR (400 MHz, CDCl₃) δ ppm 3.29 (s, 2H), 3.69 (s, 3H), 4.23 (t, J=4.55Hz, 2H), 6.30 (s, 1H), 7.05 (d, J=8.84 Hz, 1H), 7.44 (d, J=11.62 Hz,2H), 7.55 (d, J=8.34 Hz, 1H), 7.61-7.68 (m, 2H), 8.18 (t, J=7.71 Hz,1H), 8.61 (d, J=13.14 Hz, 1H).

Example 2.7 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-5-trifluoromethyl-benzamide(Compound 204)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=423 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.15 (q, J=5.56 Hz, 2H), 3.71 (s, 3H), 4.19(t, J=5.56 Hz, 2H), 6.37 (d, J=2.02 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H),7.49 (d, J=1.77 Hz, 1H), 7.62 (d, J=9.09 Hz, 1H), 7.66 (d, J=2.78 Hz,1H), 7.79 (dd, J=8.97, 2.65 Hz, 1H), 7.90 (s, 3H), 7.96-8.04 (m, 1H),8.07 (dd, J=6.06, 2.27 Hz, 1H), 10.6 (s, 1H).

Example 2.8 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-acetamide(Compound 83)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=385 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.09-3.18 (m, 2H), 3.63 (s, 2H), 3.67 (s,3H), 4.13 (t, J=5.56 Hz, 2H), 6.32 (d, J=2.02 Hz, 1H), 7.17 (d, J=9.09Hz, 1H), 7.31-7.43 (m, 4H), 7.47 (d, J=2.02 Hz, 1H), 7.54 (d, J=2.78 Hz,1H), 7.65 (dd, J=8.97, 2.65 Hz, 1H), 7.88 (br. s., 3H), 10.25 (s, 1H).

Example 2.9 Preparation of 5-Methyl-isoxazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound260)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 342 (M+H).

Example 2.10 Preparation of 5-Methyl-isoxazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound145)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 342 (M+H).

Example 2.11 Preparation of 3,5-Dimethyl-isoxazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound272)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 356 (M+H).

Example 2.12 Preparation of 5-tert-Butyl-2-methyl-furan-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 118)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 397 (M+H).

Example 2.13 Preparation of Furan-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound130)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 327 (M+H).

Example 2.14 Preparation of 2,5-Dimethyl-furan-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound142)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 355 (M+H).

Example 2.15 Preparation of5-Methyl-2-trifluoromethyl-furan-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound220)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 409 (M+H).

Example 2.16 Preparation of 1-Methyl-1H-pyrrole-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound235)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 340 (M+H).

Example 2.17 Preparation of1-tert-Butyl-5-methyl-1H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound256)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 397 (M+H).

Example 2.18 Preparation of5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound96)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 397 (M+H).

Example 2.19 Preparation of 4-Bromo-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound114)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 421 (M+H).

Example 2.20 Preparation of 3-Chloro-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound132)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 377.1 (M+H).

Example 2.21 Preparation of 4-Methyl-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound155)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 357.3 (M+H).

Example 2.22 Preparation of 2,5-Dichloro-thiophene-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound179)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 411.3 (M+H).

Example 2.23 Preparation of Thiophene-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound168)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 343 (M+H).

Example 2.24 Preparation of3-Chloro-6-fluoro-benzo[b]thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound333)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 445 (M+H).

Example 2.25 Preparation of 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 50)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 417 (M+H).

Example 2.26 Preparation of 2,2-Difluoro-benzo[1,3]dioxole-4-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 65)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 417 (M+H).

Example 2.27 Preparation of2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound80)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 407 (M+H).

Example 2.28 Preparation of 3-Methyl-benzofuran-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound273)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 391 (M+H).

Example 2.29 Preparation of1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound282)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 471 (M+H).

Example 2.30 Preparation of1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound291)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 505 (M+H).

Example 2.31 Preparation of5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound243)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 505 (M+H).

Example 2.31 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-thiophen-2-yl-benzamide(Compound 218)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 419 (M+H).

Example 2.32 Preparation of Cyclopentanecarboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound259)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 329 (M+H).

Example 2.33 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-6-trifluoromethyl-nicotinamide(Compound 105)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 406 (M+H).

Example 2.34 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide(Compound 170)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 421 (M+H).

Example 2.35 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methyl-benzamide(Compound 176)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 351 (M+H).

Example 2.36 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-propionamide(Compound 182)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS 289 (M+H).

Example 2.37 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-benzamide(Compound 219)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 373 (M+H).

Example 2.38 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide(Compound 157)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 373 (M+H).

Example 2.39 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide(Compound 293)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 355 (M+H).

Example 2.40 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methyl-benzamide(Compound 300)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 369 (M+H).

Example 2.41 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-chloro-6-fluoro-benzamide(Compound 314)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 389 (M+H).

Example 2.42 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide(Compound 312)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 423 (M+H).

Example 2.43 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-5-trifluoromethyl-benzamide(Compound 199)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 423 (M+H).

Example 2.44 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2,6-difluoro-phenyl)-acetamide(Compound 261)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 387 (M+H).

Example 2.45 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3,4,5-trimethoxy-benzamide(Compound 239)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 427 (M+H).

Example 2.46 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-cyano-benzamide(Compound 166)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 362 (M+H).

Example 2.47 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyano-benzamide(Compound 217)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 362 (M+H).

Example 2.48 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide(Compound 53)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 423 (M+H).

Example 2.49 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3,5-difluoro-benzamide(Compound 68)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 373 (M+H).

Example 2.50 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-methoxy-phenyl)-acetamide(Compound 232)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 381 (M+H).

Example 2.51 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-fluoro-phenyl)-acetamide(Compound 247)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 369 (M+H).

Example 2.52 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3-methoxy-phenyl)-acetamide(Compound 264)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z 381 (M+H).

Example 2.53 Preparation of 3-Chloro-benzo[b]thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound324)

The title compound was prepared in a similar manner as described inExample 2.1, Step B to give a white solid. LCMS m/z (%)=427 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.18 (q, J=5.05 Hz, 2H), 3.72 (s, 3H), 4.20(t, J=5.43 Hz, 2H), 6.38 (d, J=1.77 Hz, 1H), 7.27 (d, J=9.09 Hz, 1H),7.50 (d, J=1.77 Hz, 1H), 7.60-7.66 (m, 2H), 7.68 (d, J=2.27 Hz, 1H),7.83 (dd, J=8.84, 2.53 Hz, 1H), 7.89 (br. s., 3H), 7.93-7.99 (m, 1H),8.13-8.21 (m, 1H), 10.59 (s, 1H).

Example 3 Preparation of Compounds Example 3.1 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamide(Compound 75)

2,6-difluoro-4-methoxybenzoic acid (22.6 mg, 120 μmol) was weighed intoa microwave vial and CH₂Cl₂ (1 mL) was added followed by HATU (34.3 mg,90.3 μmol) and Et3N (20 μl, 144 μmol). After stirring 10 minutes,tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(20 mg, 60 μmol) was added to the solution. The reaction mixture washeated at 60° C. for one hour. Then, TFA (1 mL) was added and heated forone hour at 90° C. in order to remove the Boc-protecting group from theamine. The solvent was evaporated. The resulting oil was dissolved inDMSO (1 mL) and purified by Prep LC/MS to giveN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamidetrifluoroacetate (8.2 mg, 0.02 mmol, 34%) as a white solid. LCMS m/z(%)=403 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16 (s, 2H), 3.70 (s,3H), 3.84 (s, 3H), 4.17 (t, J=5.56 Hz, 2H), 6.36 (d, J=1.77 Hz, 1H),6.89 (d, J=9.85 Hz, 1H), 7.24 (d, J=9.09 Hz, 1H), 7.49 (d, J=1.77 Hz,1H), 7.63 (d, J=2.78 Hz, 1H), 7.77 (dd, J=9.09, 2.53 Hz, 1H), 7.89 (br.s., 3H), 10.69 (s, 1H), 13.46 (s, 1H).

Example 3.2 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-dimethylamino-benzamide(Compound 16)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z (%)=380 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.82 (s, 6H), 3.11-3.21 (m, 2H), 3.71 (s, 3H), 4.17(t, J=5.56 Hz, 2H), 6.37 (d, J=1.77 Hz, 1H), 7.13 (t, J=7.45 Hz, 1H),7.23 (d, J=9.09 Hz, 1H), 7.28 (d, J=8.08 Hz, 1H), 7.45-7.51 (m, 2H),7.67 (d, J=1.52 Hz, 1H), 7.69 (d, J=2.78 Hz, 1H), 7.83 (dd, J=9.09, 2.78Hz, 1H), 7.90 (br. s., 3H), 11.14 (s, 1H).

Example 3.3 Preparation of 5-Methyl-1H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound237)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z (%)=341 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.29 (s, 3H), 3.15 (q, J=5.56 Hz, 2H), 3.72 (s, 3H),4.16 (t, J=5.56 Hz, 2H), 6.36 (d, J=1.77 Hz, 1H), 6.51 (s, 1H), 7.20 (d,J=9.09 Hz, 1H), 7.48 (d, J=1.77 Hz, 1H), 7.77 (d, J=2.78 Hz, 1H), 7.86(br. s., 3H), 7.91 (dd, J=8.97, 2.65 Hz, 2H), 10.07 (s, 1H).

Example 3.4 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-bromo-5-methoxy-benzamide(Compound 122)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z (%)=445 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.16 (q, J=5.31 Hz, 2H), 3.70 (s, 3H), 3.81 (s, 3H),4.17 (t, J=5.56 Hz, 2H), 6.36 (d, J=1.77 Hz, 1H), 7.02 (dd, J=8.84, 3.03Hz, 1H), 7.14 (d, J=3.03 Hz, 1H), 7.23 (d, J=9.09 Hz, 1H), 7.49 (d,J=1.77 Hz, 1H), 7.60 (d, J=8.59 Hz, 1H), 7.66 (d, J=2.78 Hz, 1H), 7.80(dd, J=8.97, 2.65 Hz, 1H), 7.90 (br. s., 3H), 10.50 (s, 1H).

Example 3.5 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-4-methoxy-benzamide(Compound 253)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z (%)=445 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.17 (q, J=5.31 Hz, 2H), 3.71 (s, 3H), 3.94 (s, 3H),4.18 (t, J=5.56 Hz, 2H), 6.36 (d, J=1.77 Hz, 1H), 7.25 (dd, J=13.52,8.97 Hz, 2H), 7.49 (d, J=2.02 Hz, 1H), 7.70 (d, J=2.78 Hz, 1H), 7.86(br. s., J=9.09, 2.78 Hz, 3H), 7.86 (dd, J=9.09, 2.78 Hz, 1H), 8.01 (dd,J=8.59, 2.27 Hz, 1H), 8.23 (d, J=2.27 Hz, 1H), 10.23 (s, 1H).

Example 3.6 Preparation of 5-Methyl-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound245)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 357 (M+H).

Example 3.7 Preparation of 3-Methyl-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound73)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 357 (M+H).

Example 3.8 Preparation of 3-Ethoxy-thiophene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound88)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 387 (M+H).

Example 3.9 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-morpholin-4-yl-benzamide(Compound 4)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 422 (M+H).

Example 3.10 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-6-morpholin-4-yl-nicotinamide(Compound 268)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 423 (M+H).

Example 3.11 Preparation of4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound10)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 408 (M+H).

Example 3.12 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamide(Compound 22)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 381 (M+H).

Example 3.13 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-2-methyl-benzamide(Compound 28)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 381 (M+H).

Example 3.14 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-4-methyl-benzamide(Compound 108)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 381 (M+H).

Example 3.15 Preparation of 4-Bromo-1-methyl-1H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 193)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 419 (M+H).

Example 3.16 Preparation of 3-Methyl-3H-imidazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound126)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 341 (M+H).

Example 3.17 Preparation of 5-Bromo-furan-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound207)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 405 (M+H).

Example 3.18 Preparation of 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 222)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 389 (M+H).

Example 3.19 Preparation of 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 144)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 369 (M+H).

Example 3.20 Preparation of Thiazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound167)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 344 (M+H).

Example 3.21 Preparation of 4,5-Dichloro-isothiazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound45)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 412 (M+H).

Example 3.22 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-methoxy-benzamide(Compound 252)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 401 (M+H).

Example 3.23 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-3-methoxy-benzamide(Compound 270)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 385 (M+H).

Example 3.24 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-2-methyl-benzamide(Compound 110)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 381 (M+H).

Example 3.25 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3,5-dimethyl-benzamide(Compound 321)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 395 (M+H).

Example 3.26 Preparation of 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound330)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 355 (M+H).

Example 3.27 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methoxy-benzamide(Compound 60)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 385 (M+H).

Example 3.28 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-trifluoromethyl-benzamide(Compound 90)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 435 (M+H).

Example 3.29 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methoxy-benzamide(Compound 279)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 385 (M+H).

Example 3.30 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyclopentyloxy-4-methoxy-benzamide(Compound 288)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 451 (M+H).

Example 3.31 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 238)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 385 (M+H).

Example 3.32 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3,4-difluoro-phenyl)-acetamide(Compound 104)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 387 (M+H).

Example 3.33 Preparation of 5-Methyl-2H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound280)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z 341 (M+H).

Example 3.34 Preparation of 5-Isopropyl-2H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound58)

The title compound was prepared in a similar manner as described inExample 3.1 to give a white solid. LCMS m/z (%)=369 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.25 (d, J=6.82 Hz, 6H), 3.0 (m, 1H), 3.16 (q,J=5.56 Hz, 2H), 3.72 (s, 3H), 4.16 (t, J=5.43 Hz, 2H), 6.36 (d, J=1.77Hz, 1H), 6.54 (s, 1H), 7.20 (d, J=9.09 Hz, 1H), 7.48 (d, J=1.77 Hz, 1H),7.76 (d, J=2.53 Hz, 1H), 7.91 (br. s., 3H), 7.91 (dd, J=6.32, 2.78 Hz,1H), 10.06 (s, 1H).

Example 4 Preparation of Compounds Example 4.1 Preparation of tert-butyl2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate

Tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(265 mg, 797.2 μmol), m-anisoyl chloride (168.0 μl, 1.5 eq) andtriethylamine (266.7 μl, 2.4 eq) were taken up in 20 mL ofdichloromethane in a round bottomed flask and stirred at 22° C. for 18hr. The reaction was then concentrated and purified by columnchromatography (40-75% ethyl acetate in hexane) to afford the titlecompound as a pale yellow oil in 73.9% yield LCMS m/z (%)=467 (M+H,100). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 3.42 (q, J=5.56 Hz,2H), 3.78 (s, 3H), 3.88 (s, 3H), 4.04 (t, J=4.80 Hz, 2H), 6.28 (d, 1H),7.01 (d, J=9.09 Hz, 1H), 7.10 (dt, J=4.55, 2.53 Hz, 1H), 7.38-7.41 (m,2H), 7.43-7.45 (m, J=3.03 Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.66-7.71(m, 1H), 7.76 (s, 1H).

Example 4.2 Preparation ofN-[4-(2-Acetylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 194)

TheN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamidehydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μl, 3.0 eq)were taken up in 2 mL of dichloromethane and stirred for 15 mins. Tothis was added acetyl chloride (6.35 μl, 1.2 eq) and the reaction wasstirred at room temperature for 18 hrs. The solvents were evaporatedunder a stream of nitrogen and it was purified by HPLC. The properfractions were collected and lyophilized to afford the title compound asa white solid in 54.3% yield. LCMS m/z (%)=409 (M+H, 100). ¹H NMR (400MHz, CDCl₃) δ ppm 1.97 (s, 3H), 3.49-3.56 (m, 2H), 3.85 (s, 3 H), 3.88(s, 3H), 4.09 (t, J=5.05 Hz, 2H), 6.36 (t, J=6.32 Hz, 1H), 6.39 (d,J=2.02 Hz, 1H), 7.02 (d, J=8.59 Hz, 1H), 7.09-7.13 (m, 1H), 7.36-7.45(m, 2H), 7.61 (dd, J=9.09, 2.53 Hz, 1H), 7.69 (d, J=1.52 Hz, 1H), 7.75(d, J=2.02 Hz, 2H), 7.85 (s, 1H).

Example 4.3 Preparation of{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid ethyl ester (Compound 342)

TheN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamidehydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μl, 3.0 eq)were taken up in 2 mL of dichloromethane and stirred for 15 mins. Tothis was added ethyl chloroformate (8.58 μl, 1.2 eq) and the reactionwas stirred at room temperature for 18 hrs. The solvents were evaporatedunder a stream of nitrogen and it was purified by HPLC. The properfractions were collected and lyophilized to afford the title compound asa white solid in 52.4% yield. LCMS m/z (%)=439 (M+H, 100). ¹H NMR (400MHz, CDCl₃) δ ppm 1.23 (t, J=7.07 Hz, 3H), 3.44-3.51 (m, 2H), 3.85 (s,3H), 3.88 (s, 3H), 3.94-4.21 (m, 5H), 6.38 (d, J=2.53 Hz, 1H), 7.03 (d,J=9.60 Hz, 1H), 7.11 (dt, J=4.67, 2.27 Hz, 1H), 7.36-7.46 (m, 3H),7.62-7.72 (m, 2H), 7.83 (s, 1H)

Example 4.4 Preparation ofN-[4-[2-(2-Dimethylamino-acetylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 344)

2-(dimethylamino)acetic acid (16.0 mg, 1.25 eq), triethylamine (34.6 mL,2.0 eq) and HATU (59.0 mg, 1.25 eq) were dissolved in 3 mL ofdichloromethane and stirred at room temperature for 10 minutes. At thistimeN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamidehydrochloride (50.0 mg, 124 μmol) dissolved in 2.0 mL of dichloromethanewas added and the reaction was stirred at room temperature for 3 hr. Thesolvents were evaporated under a stream of nitrogen and it was purifiedby HPLC. The proper fractions were collected and lyophilized. It wasthen stirred overnight in 2.0M hydrochloric acid in ether (310.3 μl, 5eq). The solvents were evaporated under a stream of nitrogen andlyophilized to afford the title compound as a white solid in 43.0%yield. LCMS m/z (%)=452 (M+H, 100). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.83(s, 3H), 2.90 (s, 3H), 3.61-3.67 (m, 2H), 3.82 (s, 2H), 3.87 (s, 3H),3.88 (s, 3H), 4.07 (t, J=4.55 Hz, 2H), 6.42 (d, J=2.53 Hz, 1H), 6.99 (d,J=8.59 Hz, 1H), 7.10 (dt, J=4.55, 2.53 Hz, 1H), 7.40 (d, J=5.05 Hz, 2H),7.44 (s, 1H), 7.57 (dd, J=9.09, 2.53 Hz, 1H), 7.70 (d, J=2.53 Hz, 1H),7.82 (d, J=2.53 Hz, 1H)

Example 4.5 Preparation ofN-[4-[2-((S)-2-Acetylamino-4-methylsulfanyl-butyrylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 340)

(S)-2-acetamido-4-(methylthio)butanoic acid (17.8 mg, 1.25 eq),triethylamine (20.8 mL, 2.0 eq) and HATU (35.4 mg, 1.25 eq) weredissolved in 3 mL of dichloromethane and stirred at room temperature for10 minutes. At this timeN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamidehydrochloride (30 mg, 74.5 μmol) dissolved in 2.0 mL of dichloromethanewas added and the reaction was stirred at room temperature for 3 hr. Thesolvents were evaporated under a stream of nitrogen and it was purifiedby HPLC. The proper fractions were collected and lyophilized to affordthe title compound as a white solid in 57.3% yield. LCMS m/z (%)=540(M+H, 100). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.01 (s, 4H), 2.07 (s, 3H),2.38-2.44 (m, 2H), 3.46-3.65 (m, 2H), 3.85 (s, 3H), 3.88 (s, 3H),4.03-4.12 (m, 2H), 4.45-4.53 (m, 1H), 6.39 (d, J=2.02 Hz, 1H), 7.02 (d,J=9.60 Hz, 1H), 7.11 (dt, J=4.80, 2.53 Hz, 1H), 7.38-7.42 (m, 2H),7.43-7.46 (m, 1H), 7.63-7.71 (m, 2H), 7.86 (s, 1H)

Example 4.6 Preparation of trichloromethyl2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate

N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamidehydrochloride (80.0 mg, 198 μmol), triethylamine (277 μl, 10 eq) andtriphosgene (64.8 mg, 1.1 eq) were dissolved in 5 mL of dichloromethaneand stirred under reflux for 5 mins. The solvent was removed undervacuum and 4 mL of ethyl acetate was added. It was divided in two andused immediately in the preparation of compound 5 and 7 withoutpurification. LCMS m/z (%)=528 (M+H, 100).

Example 4.7 Preparation of{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid 4-nitro-phenyl ester (Compound 339)

Trichloromethyl2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(50.0 g, 94.74 mmol), 4-nitrophenol (14.50 g, 1.1 eq) and magnesiumoxide (1.067 mL, 1.0 eq) were taken up in 2 mL of ethyl acetate in around bottomed flask and stirred at 22° C. for 3 hr. The magnesium oxidewas filtered off. The solvent was then evaporated and it was purified byHPLC. The proper fractions were collected and lyophilized to afford thetitle compound as a white solid in 39.1% yield. LCMS m/z (%)=532 (M+H,100).

Example 4.8 Preparation of{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid 2-dimethylamino-ethyl ester (Compound 343)

Trichloromethyl2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(50.0 g, 94.74 mmol), 2-(dimethylamino)ethanol (14.50 g, 1.1 eq) andmagnesium oxide (1.067 mL, 1.0 eq) were taken up in 2 mL of ethylacetate in a round bottomed flask and stirred at 22° C. for 3 hr. Themagnesium oxide was filtered off. The solvent was then evaporated and itwas purified by HPLC. The proper fractions were collected andlyophilized to afford the title compound as a white solid in 31.3%yield. LCMS m/z (%)=482 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.82(s, 3H), 2.84 (s, 3H), 3.34 (q, J=5.05 Hz, 4H), 3.69 (s, 3H), 3.84 (s,3H), 4.06 (t, J=5.56 Hz, 2H), 4.25-4.29 (m, 2H), 6.28 (d, J=1.52 Hz,1H), 7.14-7.22 (m, 2H), 7.40 (t, J=5.56 Hz, 1H), 7.47 (d, J=2.02 Hz,3H), 7.51-7.55 (m, 1H), 7.70 (d, J=2.53 Hz, 1H), 7.84 (dd, J=8.84, 2.78Hz, 1H), 9.48-9.62 (m, 1H).

Example 4.9 Preparation of tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate

4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (3.02 g, 15.96 mmol),tert-butyl 2-bromoethylcarbamate (7.153 g, 2.0 eq) and potassiumcarbonate (4.412 g, 2.0 eq) were dissolved in 100 mL acetone andrefluxed at 60° C. for 24 h. After reaction, the potassium carbonate wasfiltered and acetone was evaporated. The residue was dissolved in 100 mLDCM and extracted with 3×100 mL 1N NaOH. Purified by columnchromatography (50-100% ethyl acetate in hexane) to afford the titlecompound as a yellow oil in 29.10% yield. LCMS m/z (%)=333 (M+H, 100).¹H NMR (400 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 3.33 (q, J=5.05 Hz, 2H),3.75 (s, 3H), 3.91 (t, J=5.05 Hz, 2H), 4.45-4.51 (m, 1H), 6.23 (d,J=2.02 Hz, 1H), 6.62 (d, J=3.03 Hz, 1H), 6.73 (dd, J=8.59, 3.03 Hz, 1H),6.85 (d, 1H), 7.52 (d, J=2.02 Hz, 1H).

Example 4.10 Preparation of 4,5-Dimethyl-furan-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound254)

4,5-dimethylfuran-2-carboxylic acid (12.65 mg, 1.2 eq), triethylamine(26.21 μl, 3.0 eq) and HATU (34.32 mg, 1.2 eq) were dissolved in 1 mL ofdichloromethane and stirred at room temperature for 20 minutes. At thistime tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (25.0 mg,75.2 μmol) dissolved in 0.5 mL of dichloromethane was added and thereaction was stirred at room temperature for 18 hr. The solvent wasevaporated under a stream of nitrogen and the residue was dissolved in0.5 mL of ethyl acetate. To this was added 2.0M hydrochloric acid inether (376 μl, 5 eq) and the reaction was stirred at room temperatureovernight. The solvent was evaporated under a stream of nitrogen and theresidue was dissolved in 1 mL of dimethylsulfoxide and purified by HPLC.The proper fractions were collected and lyophilized to afford the titlecompound as a pale yellow solid in 47.3% yield. LCMS m/z (%)=355 (M+H,100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98 (s, 3H), 2.30 (s, 3H),3.11-3.20 (m, 2H), 3.71 (s, 3H), 4.16 (t, J=5.31 Hz, 3H), 6.36 (s, 1H),7.10 (s, 1H), 7.21 (d, J=9.09 Hz, 1H), 7.49 (d, J=2.02 Hz, 1H), 7.49 (d,J=2.02 Hz, 1H), 7.68 (d, J=3.03 Hz, 1H), 7.84 (dd, J=9.09, 2.53 Hz, 1H),7.86-7.98 (m, 2H), 10.01 (s, 1H).

Example 4.11 Preparation of 4-Fluoro-5-methyl-1H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 309)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a pale yellow solid in 43.3% yield. LCMS m/z(%)=359 (M+H, 100).

Example 4.12 Preparation of 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound101)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 34.9% yield. LCMS m/z (%)=358(M+H, 100).

Example 4.13 Preparation of 4-Methyl-oxazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound113)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 28.2% yield. LCMS m/z (%)=342(M+H, 100).

Example 4.14 Preparation of 5-Isopropyl-isoxazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound131)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 33.8% yield. LCMS m/z (%)=370(M+H, 100).

Example 4.15 Preparation of 2-Methyl-furan-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound266)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a beige solid in 35.7% yield. LCMS m/z (%)=341(M+H, 100).

Example 4.16 Preparation of 4-Methyl-[1,2,3]thiadiazole-5-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 100)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a beige solid in 38.6% yield. LCMS m/z (%)=359(M+H, 100).

Example 4.17 Preparation of 5-Phenyl-isoxazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound290)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a beige solid in 26.3% yield. LCMS m/z (%)=404(M+H, 100).

Example 4.18 Preparation of 3-Phenyl-isoxazole-5-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound112)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a beige solid in 53.7% yield. LCMS m/z (%)=404(M+H, 100).

Example 4.19 Preparation of 5-Butyl-4-fluoro-1H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 318)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 36.7% yield. LCMS m/z (%)=401(M+H, 100).

Example 4.20 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-isonicotinamide(Compound 124)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a yellow solid in 13.8% yield. LCMS m/z (%)=338(M+H, 100).

Example 4.21 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3,5-dichloro-isonicotinamide(Compound 2)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 22.4% yield. LCMS m/z (%)=407(M+H ³⁵Cl, 100), 409 (M+H ³⁷Cl, 70).

Example 4.22 Preparation of Quinoline-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound211)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a yellow solid in 53.1% yield. LCMS m/z (%)=388(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.14-3.22 (m, 2H), 3.75 (s,3H), 4.22 (t, J=5.31 Hz, 2H), 6.41 (d, J=2.00 Hz, 1H), 7.29 (d, J=9.09Hz, 1H), 7.51 (d, J=2.02 Hz, 1H), 7.77 (t, J=7.58 Hz, 1H), 7.87-7.97 (m,4H), 8.08 (dd, J=9.09, 2.53 Hz, 1H), 8.14 (d, J=7.58 Hz, 1H), 8.25 (d,J=8.08 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 8.64 (d, J=8.08 Hz, 1H), 10.84(s, 1H).

Example 4.23 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-nicotinamide(Compound 221)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 23.3% yield. LCMS m/z (%)=372(M+H ³⁵Cl, 100), 374 (M+H ³⁷Cl, 34).

Example 4.24 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-dimethoxy-nicotinamide(Compound 231)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 43.4% yield. LCMS m/z (%)=398(M+H, 100).

Example 4.25 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-6-methyl-nicotinamide(Compound 241)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a yellow solid in 31.4% yield. LCMS m/z (%)=352(M+H, 100).

Example 4.26 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-6-phenoxy-nicotinamide(Compound 257)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 45.8% yield. LCMS m/z (%)=430(M+H, 100).

Example 4.27 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-6-cyano-nicotinamide(Compound 299)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a yellow solid in 13.3% yield. LCMS m/z (%)=363(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (d, J=5.56 Hz, 2H),3.71 (s, 3H), 4.20 (t, J=5.31 Hz, 2H), 6.37 (s, 1H), 7.27 (d, J=8.59 Hz,1H), 7.50 (s, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.81-7.93 (m, 4H), 8.26 (d,J=8.08 Hz, 1H), 8.52 (dd, J=8.08, 2.02 Hz, 1H), 9.23 (s, 1H), 10.70 (s,1H).

Example 4.28 Preparation of6-Acetylamino-N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 311)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 19.1% yield. LCMS m/z (%)=395(M+H, 100).

Example 4.29 Preparation of 5-Ethyl-4-fluoro-1H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 200)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 12.1% yield. LCMS m/z (%)=373(M+H, 100).

Example 4.30 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-methyl-nicotinamide(Compound 97)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 17.5% yield. LCMS m/z (%)=352(M+H, 100).

Example 4.31 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2-methoxy-phenyl)-acetamide(Compound 115)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 43.6% yield. LCMS m/z (%)=381(M+H, 100).

Example 4.32 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-benzo[1,3]dioxol-5-yl-acetamide(Compound 139)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 39.0% yield. LCMS m/z (%)=395(M+H, 100).

Example 4.33 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-methoxy-phenyl)-propionamide(Compound 162)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 34.6% yield. LCMS m/z (%)=395(M+H, 100).

Example 4.34 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(1H-indol-3-yl)-acetamide(Compound 297)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a pale yellow solid in 39.8% yield. LCMS m/z(%)=390 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.09-3.19 (m, 2H),3.67 (s, 3H), 3.71 (s, 2H), 4.13 (t, J=5.56 Hz, 2H), 6.31 (d, J=1.52 Hz,1H), 6.95-7.01 (m, 1H), 7.04-7.10 (m, 1H), 7.17 (d, J=9.09 Hz, 1H), 7.26(d, J=2.02 Hz, 1H), 7.35 (d, J=8.08 Hz, 1H), 7.46 (d, J=2.02 Hz, 1H),7.56 (d, J=2.53 Hz, 1H), 7.60 (d, J=8.08 Hz, 1H), 7.68 (dd, J=8.84, 2.78Hz, 1H), 7.84 (s, J=7.58 Hz, 2H), 10.13 (s, 1H), 10.92 (s, 1H).

Example 4.35 Preparation of 3-Methoxy-cyclohexanecarboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound8)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 13.2% yield. LCMS m/z (%)=373(M+H, 100).

Example 4.36 Preparation of 4-Methoxy-cyclohexanecarboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound136)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 21.7% yield. LCMS m/z (%)=373(M+H, 100).

Example 4.37 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-thiophen-3-yl-acetamide(Compound 215)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 41.6% yield. LCMS m/z (%)=357(M+H, 100).

Example 4.38 Preparation of5-Cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound214)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 32.5% yield. LCMS m/z (%)=385(M+H, 100).

Example 4.39 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-hydroxy-nicotinamide(Compound 62)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a pale yellow solid in 32.5% yield. LCMS m/z(%)=354 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.11-3.19 (m, 2H),3.70 (s, 3H), 4.17 (t, J=5.56 Hz, 2H), 6.37 (s, 1H), 6.58 (t, J=6.57 Hz,1H), 7.23 (d, J=8.59 Hz, 1H), 7.48 (d, J=2.02 Hz, 1H), 7.68-7.75 (m,2H), 7.82 (dt, J=6.32, 2.02 Hz, 1H), 7.85-7.93 (m, 2H), 8.44 (dd,J=7.33, 2.27 Hz, 1H), 12.17 (s, 1H), 12.76 (d, J=6.06 Hz, 1H).

Example 4.40 Preparation of(S)—N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-methoxy-2-phenyl-acetamide(Compound 230)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 24.4% yield. LCMS m/z (%)=381(M+H, 100).

Example 4.41 Preparation of 6-Oxo-1,6-dihydro-pyridine-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound134)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a pale yellow solid in 30.6% yield. LCMS m/z(%)=354 (M+H, 100).

Example 4.42 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3,4-dichloro-phenyl)-2-methoxy-acetamide(Compound 151)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 48.0% yield. LCMS m/z (%)=450(M+H ³⁵Cl, 100), 452 (M+H ³⁷Cl, 72).

Example 4.43 Preparation of 4-Chloro-1-methyl-1H-pyrazole-3-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 234)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 49.8% yield. LCMS m/z (%)=375(M+H ³⁵Cl, 100), 377 (M+H ³⁷Cl, 38). ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.16 (dt, J=10.99, 5.31 Hz, 2H), 3.72 (s, 3H), 3.94 (s, 3H), 4.17 (t,J=5.56 Hz, 2H), 6.37 (d, J=2.02 Hz, 1H), 7.20 (d, J=9.09 Hz, 1H), 7.49(d, J=2.02 Hz, 1H), 7.74 (d, J=2.53 Hz, 1H), 7.84-7.96 (m, 3H), 8.13 (s,1H), 10.24 (s, 1H).

Example 4.44 Preparation of 4-Methoxy-thiophene-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound163)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 5.0% yield. LCMS m/z (%)=373(M+H, 100).

Example 4.45 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2-ethoxy-phenyl)-acetamide(Compound 175)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a beige solid in 17.0% yield. LCMS m/z (%)=395(M+H, 100).

Example 4.46 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2,3-dimethoxy-phenyl)-acetamide(Compound 187)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 32.0% yield. LCMS m/z (%)=411(M+H, 100).

Example 4.47 Preparation of8-Methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound325)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 13.2% yield. LCMS m/z (%)=421(M+H, 100).

Example 4.48 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(5-methyl-tetrazol-1-yl)-acetamide(Compound 14)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 23.2% yield. LCMS m/z (%)=357(M+H, 100).

Example 4.49 Preparation of4-Acetyl-N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 331)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 43.7% yield. LCMS m/z (%)=379(M+H, 100).

Example 4.50 Preparation of1-Methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound255)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 52.3% yield. LCMS m/z (%)=409(M+H, 100).

Example 4.51 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-isonicotinamide(Compound 337)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a yellow solid in 45.2% yield. LCMS m/z (%)=372(M+H, 100).

Example 4.52 Preparation of 6-Methyl-pyridine-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound52)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a yellow solid in 52.5% yield. LCMS m/z (%)=352(M+H, 100).

Example 4.53 Preparation of 1H-Imidazole-4-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound251)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a white solid in 30.4% yield. LCMS m/z (%)=327(M+H, 100).

Example 4.54 Preparation of tert-butyl{2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate

N,N′-Disuccinimidyl carbonate (462 mg, 1.2 eq) was dissolved in 30 mLdimethylformamide and cooled to 0° C. To this was added the tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (500 mg,1.81 mmol) dissolved in 10 mL dimethylformamide, drop-wise over 30 mins.The solution was removed from the ice bath and stirred at roomtemperature for 2 hr, then moved to an oil bath and stirred at 65° C.for 30 minutes. It was then removed from heating and allowed to cool toroom temperature. It was used in the following step withoutpurification. LCMS m/z (%)=474 (M+H, 100).

Example 4.55 Preparation of 3,4-Dihydro-1H-isoquinoline-2-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 269)

A 2 mL aliquot of tert-butyl{2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamatein dimethylformamide (60.0 μmol) was added to1,2,3,4-tetrahydroisoquinoline (9.59 mg, 1.2 eq) and stirred at roomtemperature for 18 hr. To this was added 2.0M hydrochloric acid in ether(150 μl, 5 eq) and the reaction was stirred at room temperature for 60hr. Some of the deprotections were incomplete so 2-3 drops ofconcentrated hydrochloric acid was added to these and they were stirredfor another 24 hr. The ether and hydrochloric acid were evaporated undera stream of nitrogen and it was purified by HPLC. The proper fractionswere collected and lyophilized to afford the title compound as a whitesolid in 42.9% yield. LCMS m/z (%)=392 (M+H, 100). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.85 (t, J=5.81 Hz, 2H), 3.09-3.17 (m, 2H), 3.69 (t,J=5.6 Hz, 2H), 3.69 (s, 3H), 4.12 (t, J=5.56 Hz, 2H), 4.63 (s, 2H), 6.32(d, J=2.02 Hz, 1H), 7.13 (d, J=9.09 Hz, 1H), 7.19 (s, 3H), 7.43 (d,J=2.53 Hz, 1H), 7.47 (d, J=1.52 Hz, 1H), 7.57 (dd, J=9.09, 3.03 Hz, 1H),7.87 (s, 2H), 8.60 (s, 1H).

Example 4.56 Preparation of 3,4-Dihydro-2H-quinoline-1-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound109)

The title compound was prepared in a similar manner as described inExample 4.55 to afford an orange oil in 47.1% yield. LCMS m/z (%)=392(M+H, 100).

Example 4.57 Preparation of 2,3-Dihydro-indole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound133)

The title compound was prepared in a similar manner as described inExample 4.55 to afford a white solid in 37.1% yield. LCMS m/z (%)=378(M+H, 100).

Example 4.58 Preparation of 1,3-Dihydro-isoindole-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound156)

The title compound was prepared in a similar manner as described inExample 4.55 to afford a white solid in 4.8% yield. LCMS m/z (%)=378(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.10-3.18 (m, 2H), 3.70 (s,3H), 4.13 (t, J=5.56 Hz, 2H), 4.76 (s, 4H), 6.33 (d, J=2.02 Hz, 1H),7.16 (d, J=9.09 Hz, 1H), 7.29-7.39 (m, 3H), 7.48 (d, J=2.02 Hz, 1H),7.52 (d, J=2.53 Hz, 1H), 7.66 (dd, J=9.09, 3.03 Hz, 1H), 7.84 (s, 1H),7.89 (s, 2H), 8.40 (s, 1H).

Example 4.59 Preparation of2,3,4,5-Tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound294)

The title compound was prepared in a similar manner as described inExample 4.55 to afford an orange oil in 33.6% yield. LCMS m/z (%)=407(M+H, 100).

Example 4.60 Preparation of Octahydro-isoquinoline-2-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound306)

The title compound was prepared in a similar manner as described inExample 4.55 to afford a white solid in 10.4% yield. LCMS m/z (%)=398(M+H, 100).

Example 4.61 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-oxo-2-p-tolyl-acetamide(Compound 20)

The 2-oxo-2-p-tolylacetic acid (14.82 mg, 1.2 eq),), triethylamine(31.45 μl, 3.0 eq) and HATU (34.32 mg, 1.2 eq) were dissolved in 1 mL ofdichloromethane and stirred at room temperature for 20 minutes. At thistime tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (25.0 mg,75.2 μmol) dissolved in 0.5 mL of dichloromethane was added and thereaction was stirred at room temperature for 18 hr. The solvent wasevaporated under a stream of nitrogen and the residue was dissolved in0.5 mL of ethyl acetate. To this was added 2.0M hydrochloric acid inether (188 μl, 5 eq) and the reaction was stirred at room temperatureovernight. The solvent was evaporated under a stream of nitrogen and theresidue was dissolved in 1 mL of dimethylsulfoxide and purified by HPLC.The proper fractions were collected and lyophilized to afford the titlecompound as a white solid in 32.2% yield. LCMS m/z (%)=379 (M+H, 100. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.42 (s, 3H), 3.12-3.21 (m, 2H), 3.71 (s,3H), 4.19 (t, J=5.56 Hz, 2H), 6.37 (d, J=1.52 Hz, 1H), 7.26 (d, J=9.09Hz, 1H), 7.42 (d, J=8.59 Hz, 2H), 7.49 (d, J=2.02 Hz, 1H), 7.70 (d,J=2.53 Hz, 1H), 7.82 (dd, J=9.09, 2.53 Hz, 1H), 7.97 (d, J=8.08 Hz, 2H),10.96 (s, 1H).

Example 4.62 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-phenyl-acetamide(Compound 125)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 34.0% yield. LCMS m/z (%)=351(M+H, 100).

Example 4.63 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3-chloro-phenyl)-acetamide(Compound 178)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 44.3% yield. LCMS m/z (%)=385(M+H ³⁵Cl, 100), 387 (M+H ³⁷Cl, 37).

Example 4.64 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2-chloro-phenyl)-acetamide(Compound 38)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 45.4% yield. LCMS m/z (%)=385(M+H ³⁵Cl, 100), 387 (M+H ³⁷Cl, 36).

Example 4.65 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2-fluoro-phenyl)-acetamide(Compound 143)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 70.7% yield. LCMS m/z (%)=369(M+H, 100).

Example 4.66 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-m-tolyl-acetamide(Compound 42)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 69.8% yield. LCMS m/z (%)=365(M+H, 100).

Example 4.67 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-o-tolyl-acetamide(Compound 154)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 52.5% yield. LCMS m/z (%)=365(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29 (s, 3H), 3.10-3.16 (m,2H), 3.66 (s, 2H), 3.67 (s, 3H), 4.13 (t, J=5.56 Hz, 2H), 6.31 (s, 1H),7.09-7.19 (m, 4H), 7.22-7.25 (m, 1H), 7.46 (d, J=2.02 Hz, 1H), 7.55 (d,J=2.53 Hz, 1H), 7.66 (dd, J=9.09, 2.53 Hz, 1H), 7.87 (s, 2H), 10.21 (s,1H).

Example 4.68 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3-trifluoromethyl-phenyl)-acetamide(Compound 184)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 40.4% yield. LCMS m/z (%)=419(M+H, 100).

Example 4.69 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2-trifluoromethyl-phenyl)-acetamide(Compound 210)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 43.9% yield. LCMS m/z (%)=419(M+H, 100).

Example 4.70 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-methoxy-phenyl)-2-oxo-acetamide(Compound 26)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 31.7% yield. LCMS m/z (%)=395(M+H, 100).

Example 4.71 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(1H-indol-3-yl)-propionamide(Compound 225)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 65.0% yield. LCMS m/z (%)=404(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.67 (t, J=7.83 Hz, 2H),3.02 (t, J=7.58 Hz, 2H), 3.11-3.17 (m, 2H), 3.68 (s, 3H), 4.13 (t,J=5.56 Hz, 2H), 6.33 (d, J=2.02 Hz, 1H), 6.98 (ddd, J=8.08, 7.07, 1.01Hz, 1H), 7.07 (dt, J=7.58, 1.01 Hz, 1H), 7.13 (d, J=2.53 Hz, 1H), 7.17(d, J=8.59 Hz, 1H), 7.33 (d, J=8.08 Hz, 1H), 7.48 (d, J=2.02 Hz, 1H),7.53-7.59 (m, 2H), 7.66 (dd, J=9.09, 2.53 Hz, 1H), 7.87 (s, 2H), 9.96(s, 1H), 10.78 (s, 1H).

Example 4.72 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyclohexyl-propionamide(Compound 240)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 47.2% yield. LCMS m/z (%)=371(M+H, 100).

Example 4.73 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-benzo[d]isoxazol-3-yl-acetamide(Compound 148)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 38.3% yield. LCMS m/z (%)=392(M+H, 100).

Example 4.74 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3,5-dimethyl-pyrazol-1-yl)-acetamide(Compound 262)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 93.2% yield. LCMS m/z (%)=369(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (s, 3H), 2.20 (s, 3H),3.11-3.18 (m, 2H), 3.68 (s, 3H), 4.15 (t, J=5.56 Hz, 2H), 4.82 (s, 2H),5.83 (s, 1H), 6.33 (d, J=1.52 Hz, 1H), 7.20 (d, J=9.09 Hz, 1H), 7.48 (d,J=2.02 Hz, 1H), 7.55 (d, J=3.03 Hz, 1H), 7.65 (dd, J=9.09, 2.53 Hz, 1H),7.85 (s, 2H), 10.34 (s, 1H).

Example 4.75 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(2,4-difluoro-phenyl)-acetamide(Compound 102)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 63.6% yield. LCMS m/z (%)=387(M+H, 100).

Example 4.76 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3-fluoro-phenyl)-acetamide(Compound 120)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 58.8% yield. LCMS m/z (%)=369(M+H, 100).

Example 4.77 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-fluoro-phenyl)-2-oxo-acetamide(Compound 32)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 32.9% yield. LCMS m/z (%)=383(M+H, 100).

Example 4.78 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide(Compound 165)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 30.2% yield. LCMS m/z (%)=419(M+H, 100).

Example 4.79 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-2-oxo-acetamide(Compound 202)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 28.4% yield. LCMS m/z (%)=399(M+H ³⁵Cl, 100), 401 (M+H ³⁷Cl, 38).

Example 4.80 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(3-fluoro-4-methoxy-phenyl)-acetamide(Compound 229)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 85.0% yield. LCMS m/z (%)=399(M+H, 100).

Example 4.81 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-5-methoxy-benzamide(Compound 249)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 64.1% yield. LCMS m/z (%)=385(M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.12-3.20 (m, 2H), 3.70 (s,3H), 3.80 (s, 3H), 4.17 (t, J=5.56 Hz, 2H), 6.36 (s, 1H), 7.08-7.19 (m,2H), 7.21-7.32 (m, 2H), 7.49 (d, J=2.02 Hz, 1H), 7.68 (d, J=3.03 Hz,1H), 7.81 (dd, J=9.09, 2.53 Hz, 1H), 7.88 (s, 2H), 10.42 (s, 1H).

Example 4.82 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-bicyclo[2.2.1]hept-2-yl-acetamide(Compound 95)

The title compound was prepared in a similar manner as described inExample 4.61 to afford a white solid in 48.1% yield. LCMS m/z (%)=369(M+H, 100).

Example 4.83 Preparation of tert-butyl{2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate

N,N′-Disuccinimidyl carbonate (262 mg, 1.2 eq) was dissolved in 6 mLdimethylformamide and cooled to 0° C. To this was added the tert-butyl2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (242 mg,0.95 mmol) dissolved in 4 mL dimethylformamide, drop-wise over 30 mins.The solution was removed from the ice bath and stirred at roomtemperature for 2 hr, then moved to an oil bath and stirred at 65° C.for 30 minutes. The mixture was used without further purification.

Example 4.84 Preparation of 4-Chloro-2,3-dihydro-indole-1-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 326)

A 1 mL aliquot of tert-butyl{2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamatein dimethylformamide (78.8 μmol) was added to 4-chloroindoline (14.52mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added2.0M hydrochloric acid in ether (197 μl, 5 eq) and the reaction wasstirred at room temperature for 24 hr (2-3 drops of concentratedhydrochloric acid was added if the deprotection was incomplete and theresulting mixture was stirred for another 24 hr). The ether andhydrochloric acid were evaporated under a stream of nitrogen and theresulting material was purified by HPLC. The proper fractions werecollected and lyophilized to afford the title compound as a white solidin 43.5% yield. LCMS m/z (%)=412 (M+H ³⁵Cl, 100), 414 (M+H ³⁷Cl, 36). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.10-3.24 (m, 4H), 3.71 (s, 3H), 4.13-4.21(m, 4H), 6.34 (d, J=2.02 Hz, 1H), 6.96 (d, J=8.08 Hz, 1H), 7.13-7.21 (m,2H), 7.48-7.50 (m, 2H), 7.64 (dd, J=8.84, 2.78 Hz, 1H), 7.81 (d, J=7.58Hz, 1H), 7.92 (s, 2H), 8.63 (s, 1H).

Example 4.85 Preparation of 6-Fluoro-2,3-dihydro-indole-1-carboxylicacid [4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 183)

The title compound was prepared in a similar manner as described inExample 4.84 to afford a white solid in 32.1% yield. LCMS m/z (%)=396(M+H, 100).

Example 4.86 Preparation of 2-Oxo-1,2-dihydro-pyridine-3-carboxylic acid[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (Compound213)

The title compound was prepared in a similar manner as described inExample 4.10 to afford a pale yellow solid in 13.8% yield. LCMS m/z(%)=354 (M+H, 100).

Example 5 Preparation of Compounds Example 5.1 Preparation ofN-[4(R)-2-Amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 79) Step A: Preparation of the intermediateN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide

4-Amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenol (2.0 g, 8.94 mmol)was suspended in anhydrous CH₂Cl₂ (75 mL). The suspension was made todissolve by the adding anhydrous DMF (5 mL) and briefly heating thesolution using a heat gun (˜50° C.). 2-Fluoro-4-methoxybenzoic acid(1.52 g, 8.94 mmol), DIEA (2.34 mL, 13.4 mmol) and HATU (4.08 g, 10.7mmol) were added to the solution. The reaction was stirred at roomtemperature for 2 hours. After this time, the reaction was extracted(120 mL each of H₂O/CH₂Cl₂). The aqueous layer was extracted once morewith CH₂Cl₂ (120 mL). The combined organic layer was dried over MgSO₄,filtered, and concentrated. The product was purified by columnchromatography (0, 20, 40, 50, 70% EtOAc/Hexanes) to yieldN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide(2.88 g, 7.66 mmol, 77.1%) as a colorless oil that turned solid uponstanding. LCMS m/z 376.1 (M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.76 (s,3H), 3.90 (s, 3H), 6.87 (dd, J=33.09, 2.53 Hz, 1H), 6.87 (dd, J=11.49,2.40 Hz, 1H), 7.00 (d, J=8.59 Hz, 1H), 7.54 (s, 1H), 7.55 (d, J=2.53 Hz,1H), 7.66 (dd, J=8.84, 2.53 Hz, 1H), 7.76 (t, J=8.72 Hz, 1H).

Step B: Preparation ofN-[4(R)-2-Amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 79)

N-(3-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide(50.0 mg, 133 μmol) and triphenylphosphine (52.3 mg, 200 μmol) wereweighed into a vial and anhydrous THF (0.5 mL) was added. The mixturewas cooled on an ice bath and DIAD (38.8 μl, 200 μmol) was added. Thesolution was stirred at 0° C. for a half hour and then (R)-tert-butyl1-hydroxypropan-2-ylcarbamate (35.0 mg, 200 μmol), pre-dissolved in THF(0.3 mL) was added. The reaction was warmed to r.t. and stirred for 4hours. The crude LC/MS showed that some product formed (˜60% complete,as judged from the LC/MS). Pushing the reaction by heating or extendingthe run time did not seem to improve the yield. Thus, the solvent wasevaporated, the resulting oil was re-dissolved in CH₂Cl₂ (0.5 mL) andTFA (0.5 mL) was added (in order to remove the Boc-protecting group fromthe amine). The reaction was stirred overnight at room temperature. Thenext day, the solvent was evaporated and the oil was dissolved in DMSO(1 mL). The product was purified by Prep LC/MS (0-60% B, 30 min) toyieldN-[4-((R)-2-amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamidetrifluoroacetate (11.0 mg, 1.83 mmol, 15.0%) as a colorless oil. LCMSm/z 433.5 (M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.18-1.43 (m, 3H),3.59-3.69 (m, 1H), 3.76 (s, 3H), 3.90 (s, 3H), 4.00-4.30 (m, 2H), 6.86(dd, J=13.01, 2.40 Hz, 1H), 6.91 (dd, J=8.59, 2.53 Hz, 1H), 7.30 (dd,J=9.09, 2.27 Hz, 1H), 7.60 (s, 1H), 7.67 (d, J=2.78 Hz, 1H), 7.77 (t,J=8.72 Hz, 1H), 7.89 (dt, J=9.03, 2.18 Hz, 1H).

Example 5.2 Preparation of 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylicacid [4-((R)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 1) Step A: Preparation of intermediate (R)-tert-butyl1-bromopropan-2-ylcarbamate

A solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (100 mg, 571μmol) and carbon tetrabromide (303 mg, 913 μmol) was cooled on an icebath. Triphenylphosphine (299 mg, 1141 μmol) was added and the reactionwas stirred for 10 min. The reaction was then allowed to warm to r.t.and stirred for 18 hours. After this time, a TLC suggested that thereaction was complete (silica, 50% EtOAc/Hexanes, Ninhydrin stain). Thesolvent was removed and the product purified by column chromatography(0, 5, 10, 15, 20% EtOAc/Hexanes) to yield (R)-tert-butyl1-bromopropan-2-ylcarbamate (67.1 mg, 0.28 mmol, 49.3%) as a colorlessoil that turned solid upon standing. LCMS 238.1 (M+H); ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.23 (d, J=6.57 Hz, 3H), 1.46 (s, 9H), 3.44 (dd, J=5.56,1.77 Hz, 2H), 3.71-3.92 (m, 1H).

Step B: Preparation of intermediate tert-butyl(R)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate

4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (500 mg, 2643 μmol),(R)-tert-butyl 1-bromopropan-2-ylcarbamate (755 mg, 3171 μmol) andcesium carbonate (1205 mg, 3700 μmol) were weighed into a vial withanhydrous acetone (3.0 mL). The reaction was heated in a microwave at100° C. for an hour. After this time, the crude LC/MS showed that thereaction was nearly complete. Thus, the solvent was evaporated and theresulting material was extracted (3 mL each of H₂O and CH₂Cl₂). Theaqueous layer was extracted again with CH₂Cl₂ (3 mL). The combinedorganic layer was dried over MgSO₄, filtered, and concentrated. Theproduct was purified by column chromatography (0, 20, 50, 70, 100%EtOAc/Hexanes) to yield tert-butyl(R)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate(487 mg, 1.41 mmol, 50.7%) as a light brown colored oil. LCMS m/z 347.1(M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm 0.92 (d, J=6.57 Hz, 3H), 1.32 (s,9H), 3.60 (s, 3H), 3.69-3.76 (m, 1H), 3.79-3.94 (m, 2H), 6.13 (d, J=1.77Hz, 1H), 6.57 (d, J=2.78 Hz, 1H), 6.72 (dd, J=8.59, 2.78 Hz, 1H), 6.83(d, J=8.84 Hz, 1H), 7.36 (d, J=2.02 Hz, 1H).

Step C: Preparation of 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid[4-((R)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 1)

To a solution of tert-butyl(R)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate(21.1 mg, 60.9 μmol) in anhydrous CH₂Cl₂ (0.5 mL) was added DIEA (13.8μl, 79.2 μmol) and 2,2-difluorobenzo[d][1,3]dioxole-4-carbonyl chloride(14.8 mg, 66.9 μmol). The reaction mixture was heated briefly with aheat gun (˜50° C.) and then stirred at r.t. for 4 hours. After thistime, the crude LC/MS showed that the reaction was fairly complete.Thus, the solvent was evaporated, the resulting oil was re-dissolved inCH₂Cl₂ (0.5 mL) and TFA (0.5 mL) was added (in order to remove theBoc-protecting group from the amine). The reaction was stirred overnightat room temperature. The next day, the solvent was evaporated and theoil was dissolved in DMSO (1 mL). The product was purified by Prep LC/MS(5-60% B, 30 minutes) to afford2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid[4-((R)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amidetrifluoroacetate (11.8 mg, 0.021 mmol, 35.7%) as a white solid that wasvery hygroscopic. LCMS m/z 431.3 (M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm1.32 (d, J=6.57 Hz, 3H), 3.57-3.69 (m, 1H), 3.79 (s, 3H), 4.07 (dd,J=10.36, 6.57 Hz, 1H), 4.17 (dd, J=10.36, 4.30 Hz, 1H), 6.43 (d, J=1.77Hz, 1H), 7.27 (d, J=9.09 Hz, 1H), 7.32 (t, J=8.08 Hz, 1H), 7.43 (dd,J=8.08, 1.01 Hz, 1H), 7.58 (d, J=2.02 Hz, 1H), 7.60 (dd, J=8.08, 1.26Hz, 1H), 7.69 (d, J=2.53 Hz, 1H), 7.84 (dd, J=8.84, 2.78 Hz, 1H).

Example 5.3 Preparation of 2,2-Difluoro-benzo[1,3]dioxole-4-carboxylicacid [4-((R)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 76)

The title compound was prepared in a similar manner as described inExample 5.2, Step C to give a white solid. LCMS m/z 431.2 (M+H).

Example 5.4 Preparation ofN-[4-((R)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 7)

The title compound was prepared in a similar manner as described inExample 5.2, Step C to give a white solid. LCMS m/z 381.3 (M+H); ¹H NMR(400 MHz, MeOH-d₄) δ ppm 1.31 (d, J=6.82 Hz, 3H), 3.58-3.68 (m, 1H),3.78 (s, 3H), 3.88 (s, 3H), 4.06 (dd, J=10.36, 6.32 Hz, 1H), 4.15 (dd,J=10.36, 4.29 Hz, 1H), 6.42 (d, J=2.02 Hz, 1H), 7.13-7.19 (m, 1H), 7.25(d, J=9.09 Hz, 1H), 7.44 (t, J=7.96 Hz, 1H), 7.48-7.54 (m, 2H), 7.57 (d,J=2.02 Hz, 1H), 7.69 (d, J=2.53 Hz, 1H), 7.84 (dd, J=8.97, 2.65 Hz, 1H).

Example 5.5 Preparation ofN-[4-((R)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide(Compound 13)

The title compound was prepared in a similar manner as described inExample 5.2, Step C to give a white solid. LCMS m/z 435.3 (M+H); ¹H NMR(400 MHz, MeOH-d₄) δ ppm 1.32 (d, J=6.82 Hz, 3H), 3.59-3.68 (m, 1H),3.79 (s, 3H), 4.07 (dd, J=10.36, 6.57 Hz, 1H), 4.16 (dd, J=10.36, 4.29Hz, 1H), 6.42 (d, J=2.02 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.44 (d,J=8.08 Hz, 2H), 7.57 (d, J=2.02 Hz, 1H), 7.70 (d, J=2.78 Hz, 1H), 7.84(dd, J=8.97, 2.65 Hz, 1H), 8.07 (d, J=8.84 Hz, 2H).

Example 5.6 Preparation of 2,5-Dichloro-thiophene-3-carboxylic acid[4-((R)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 19)

The title compound was prepared in a similar manner as described inExample 5.2, Step C to give a white solid. LCMS m/z 425.1 (M+H); ¹H NMR(400 MHz, MeOH-d₄) δ ppm 1.31 (d, J=6.57 Hz, 3H), 3.57-3.68 (m, 1H),3.77 (s, 3H), 4.03-4.08 (m, J=10.36, 6.57 Hz, 1H), 4.15 (dd, J=10.36,4.29 Hz, 1H), 6.41 (d, J=2.02 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H), 7.27 (s,1H), 7.57 (d, J=1.77 Hz, 1H), 7.63 (d, J=2.78 Hz, 1H), 7.81 (dd, J=8.97,2.65 Hz, 1H).

Example 5.7 Preparation ofN-[4-Carbamimidoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 172) Step A: Preparation of intermediateN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(cyanomethoxy)phenyl)-2-fluoro-4-methoxybenzamide

To a solution ofN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide(104 mg, 276.8 μmol) in anhydrous acetone (1 mL) was added cesiumcarbonate (108.2 mg, 332.1 μmol) and 2-bromoacetonitrile (38.56 μl,553.5 μmol). The reaction was heated in the microwave at 100° C. for ahalf hour. After this time, a crude LC/MS revealed that the reaction wascomplete. Thus, the solvent was evaporated and the reaction wasextracted (2 mL each of H₂O/CH₂Cl₂). The aqueous layer was extractedagain (2 mL CH₂Cl₂). The combined organic layer was dried over MgSO₄,filtered, and concentrated. The product was purified by columnchromatography (0, 20, 50, 70, 100% EtOAc/Hexanes) to yieldN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide(88 mg, 203.2 μmol, 73.4%) as a white solid. LCMS m/z 415.3 (M+H); ¹HNMR (400 MHz, MeOH-d₄) δ ppm 3.75 (s, 3H), 3.91 (s, 3H), 5.06 (s, 2H),6.86 (dd, J=12.88, 2.27 Hz, 1H), 6.91 (dd, J=8.72, 2.40 Hz, 1H), 7.36(d, J=8.84 Hz, 1H), 7.58 (s, 1H), 7.73 (d, J=2.53 Hz, 1H), 7.78 (t,J=8.59 Hz, 1H), 7.92 (dd, J=8.97, 2.65 Hz, 1H).

Step B: Preparation ofN-[4-Carbamimidoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 172)

N-(3-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide(20 mg, 48.2 μmol) was weighed into a vial with MeOH (1 mL). Potassiummethoxide (0.744 mg, 10.6 μmol) was added and the reaction was heated ina microwave at 100° C. for 625 sec. Ammonium chloride (2.84 mg, 53.0μmol) was added and the reaction was again heated in a microwave at 80°C. for 720 sec. After this time, the crude LC/MS showed that thereaction had fairly cleanly formed the desired intermediate in around80% yield. Thus, the reaction solvent was evaporated and the resultingoil was redissolved in DMSO (1 mL). The title compound was purified byPrep LC/MS (5-50% B, 30 min) to affordN-[4-carbamimidoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamidetrifluoroacetate (17.5 mg, 32.1 μmol, 66.5%) as a white solid. LCMS m/z432.4 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.68 (s, 3H), 3.84 (s, 3H),4.83 (d, J=14.15 Hz, 1H), 4.91 (d, J=14.15 Hz, 1H), 6.91 (dd, J=8.72,2.40 Hz, 1H), 6.98 (dd, J=12.63, 2.53 Hz, 1H), 7.22 (d, J=9.09 Hz, 1H),7.65 (t, J=8.59 Hz, 1H), 7.67 (s, 1H), 7.71 (d, J=2.53 Hz, 1H), 7.89(dd, J=8.97, 2.65 Hz, 1H), 8.98 (s, 2H), 9.06 (s, 2H), 10.32 (s, 1H).

Example 5.8 Preparation ofN-[4-(2-Amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 338) Step A: Preparation of intermediate2-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoic acid

A solution of 2-amino-4,4,4-trifluorobutanoic acid (1.2 g, 7.64 mmol) indry CH₂Cl₂ (15 mL) was cooled in an ice bath. Di-tert-butyl dicarbonate(1.80 mL, 8.40 mmol) was added and the reaction stirred for 10 min at 0°C. After this time, the reaction was allowed to warm to r.t. andstirring continued for 2 hours. The solvent was evaporated and thereaction was extracted (50 mL each of H₂O/NaHCO₃ and CH₂Cl₂). Theaqueous layer was extracted again (2×50 mL CH₂Cl₂). The combined organiclayer was dried and concentrated yielding2-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoic acid (1.94 g, 7.39 mmol,96.8% yield) as a white solid. The product was carried forward withoutfurther purification. LCMS 258.3 (M+H).

Step B: Preparation of intermediate tert-butyl4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate

A solution of 2-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoic acid (1.64g, 6.38 mmol) and DIEA (1.33 mL, 7.65 mmol) in anhydrous THF (15 mL) wascooled on an ice bath. Ethyl chloroformate (0.674 mL, 7.01 mmol) wasadded slowly via syringe. After the addition, the reaction mixture waswarmed to r.t. and stirred for 2 hours (a white solid ppt formed in thistime). After 2 hours, the precipitate was filtered and washed withanhydrous THF (4 mL). Lithium borohydride (6.38 mL, 12.8 mmol) wasslowly added to the filtrate (vigorous bubbling was observed). Thesolution was stirred for 2 hours and the reaction progress was checkedby crude LC/MS. Once the reaction was complete, most of the THF solventwas evaporated and an extraction was performed (100 mL each of H₂O/NaCland EtOAc). The aqueous layer was extracted again (2×100 mL EtOAc). Thecombined organic layer was dried over MgSO₄, filtered, and concentrated.The product was purified by column chromatography (0, 20, 50, 60, 70%EtOAc/Hexanes) to yield tert-butyl4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (1.24 g, 5.10 mmol, 80.0%)as a white solid. LCMS 244.0 (M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.45(s, 9H), 2.21-2.38 (m, 1H), 2.41-2.57 (m, 1H), 3.44 (dd, J=11.12, 6.57Hz, 1H), 3.55 (dd, J=11.12, 5.05 Hz, 1H), 3.84-3.97 (m, 1H).

Step C: Preparation ofN-[4-(2-Amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 338)

N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide(20.0 mg, 53.2 μmol) was dissolved in anhydrous THF (0.3 mL).Triphenylphosphine (15.4 mg, 58.5 μmol), pre-dissolved in anhydrous THF(0.1 mL) was added to theN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide/THFsolution. The reaction was stirred for 5 minutes and then DIAD (16.6 μl,85.2 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to thereaction. The mixture was stirred at r.t. for 5 more minutes and thentert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (16.2 mg, 66.5μmol), pre-dissolved in anhydrous THF (0.1 mL) was added. The reactionwas then stirred for 4 hours and checked by LC/MS. While the reactionhad not gone to completion, pushing the reaction by heating or extendingthe reaction time did not seem to improve the yield. Thus, the solventwas evaporated, the resulting oil re-suspended in CH₂Cl₂ (0.5 mL) andTFA (20.5 μl, 266 μmol) was added (to remove the Boc-protecting groupfrom the amine). The reaction was stirred overnight at room temperature.The next day, the solvent was removed and the resulting oil wasre-dissolved in DMSO (1 mL). The product was purified by Prep LC/MS(0-50% B, 30 min) to yieldN-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamidetrifluoroacetate (8.1 mg, 13.0 μmol, 24.5%) as a colorless oil. LCMS m/z501.3 (M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.48-2.86 (m, 2H), 3.75 (d,J=2.78 Hz, 3H), 3.87-3.97 (m, 1H), 3.89 (s, 3H), 4.10-4.43 (m, 2H), 6.85(dd, J=12.88, 2.27 Hz, 1H), 6.91 (dd, J=8.72, 2.40 Hz, 1H), 7.30 (dd,J=9.09, 2.27 Hz, 1H), 7.61 (d, J=2.53 Hz, 1H), 7.65-7.69 (m, 1H), 7.76(t, J=8.59 Hz, 1H), 7.90 (dd, J=8.97, 2.65 Hz, 1H).

Example 5.9 Preparation ofN-[4-((S)-2-Amino-4-methanesulfonyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 59) Step A: Preparation of intermediate (S)-tert-butyl1-hydroxy-4-(methylsulfonyl)butan-2-ylcarbamate

The title compound was prepared in a similar manner as described inExample 5.8, Step B to give a colorless oil that turned solid uponstanding. LCMS m/z 268.0 (M+H); ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.46 (s,9H), 1.81-1.93 (m, 1H), 2.06-2.18 (m, 1H), 2.99 (s, 3H), 3.12-3.24 (m,2H), 3.46-3.52 (m, J=11.12, 6.06 Hz, 1H), 3.56 (dd, J=11.12, 5.05 Hz,1H), 3.60-3.71 (m, 1H).

Step B: Preparation ofN-[4-((S)-2-Amino-4-methanesulfonyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 59)

The title compound was prepared in a similar manner as described inExample 5, Step C to give a white solid. LCMS m/z 525.7 (M+H); ¹H NMR(400 MHz, MeOH-d₄) δ ppm 2.13-2.30 (m, 2H), 3.02 (d, J=6.06 Hz, 3H),3.13-3.26 (m, 2H), 3.71-3.80 (m, 1H), 3.76 (s, 3H), 3.90 (s, 3H),4.10-4.35 (m, 2H), 6.85 (dd, J=13.14, 2.27 Hz, 1H), 6.91 (dd, J=8.59,2.27 Hz, 1H), 7.30 (dd, J=8.97, 5.94 Hz, 1H), 7.61 (d, J=3.28 Hz, 1H),7.65 (d, J=2.53 Hz, 1H), 7.76 (t, J=8.59 Hz, 1H), 7.84-7.98 (m, 1H).

Example 5.10 Preparation ofN-[4-Carbamoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 146)

To a mixture ofN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide(51 mg, 0.13 mmol) and potassium carbonate (27 mg, 0.20 mmol) in acetone(1 mL) was added 2-bromoacetamide (27 mg, 0.20 mmol). The resultantmixture was heated to 65° C. for 1 hour. Cooled to room temperature andpartitioned between EtOAc and water. Layers were separated. The organiclayer was washed with water (2×) and brine, dried (MgSO₄) and reduced togive the title compound as a white solid (49 mg, 83%). LCMS m/z (%)=453(M+H ³⁵Cl, 100), 455 (M+H ³⁷Cl, 30). ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.73 (s, 3H), 4.46-4.61 (m, 2H), 7.09 (d, J=9.09 Hz, 1H), 7.24 (s, 1H),7.38 (s, 1H), 7.65 (s, 1H), 7.72 (d, J=2.78 Hz, 1H), 7.73-7.84 (m, 1H),7.87 (dd, J=8.97, 2.65 Hz, 1H), 7.97 (d, J=6.57 Hz, 1H), 8.21-8.36 (m,2H), 10.53 (s, 1H).

Example 5.11 Preparation ofN-[4-Carbamoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 169)

The title compound was prepared in a similar manner as described inExample 5.10 to give the title compound as a white solid (31.1 mg,74.9%). LCMS m/z (%)=415 (M+H ³⁵Cl, 100), 417 (M+H ³⁷Cl, 30). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.73 (s, 3H), 3.83 (s, 3H), 4.46-4.60 (m, 2H),7.07 (d, J=9.09 Hz, 1H), 7.16 (dd, J=8.21, 2.15 Hz, 1H), 7.22 (br. s.,1H), 7.38 (br. s., 1H), 7.45 (t, J=7.83 Hz, 1H), 7.48 (s, 1H), 7.54 (d,J=7.58 Hz, 1H), 7.64 (s, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.87 (dd, J=9.09,2.53 Hz, 1H), 10.28 (s, 1H).

Example 6 Preparation of Compounds Example 6.1 Preparation of2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid[4-((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 191) Step A: Preparation of the intermediate(S)-2-(tert-butoxycarbonyl)propyl methanesulfonate

Methane sulfonyl chloride (1.33 mL, 17.1 mmol) was added to a solutionof (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (2.0 g, 11.4 mmol) andTEA (3.18 mL, 22.8 mmol) in DCM. The reaction was stirred at roomtemperature for 1 hour. At the completion of the reaction, the mixturewas diluted with DCM; washed with water and dried with magnesiumsulfate. The organic solvent was evaporated to dryness to afford thetitle compound as a white solid in 97.5% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.06 (d, J=6.82 Hz, 3H), 1.38 (s, 9H), 3.17 (s, 3H),3.68-3.81 (m, 1H), 4.04 (d, J=5.81 Hz, 2H), 6.96 (d, J=7.83 Hz, 1H).

Step B: Preparation of the intermediate tert-butyl(S)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate

4-Amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (300.00 mg, 1585.5 μmol),methanesulfonic acid 2-(S)-tert-butoxycarbonylamino-propyl ester (602.45mg, 2378.3 μmol) and Cesium carbonate (1033.2 mg, 3171.0 μmol) weredissolved in acetone, and heated in the microwave at 130 C for 1 hour.The reaction mixture was filtered and the filtrate removed under vacuum.The residue was dissolved in DCM; washed with 1N NaOH (3×) and thenremoved under vacuum to yield a brownish residue in 34.6% yield. LCMSm/z=347.3 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.32 Hz,3H), 1.38 (s, 9H), 3.65 (s, 3H), 3.67-3.77 (m, 3H), 6.23 (d, J=1.77 Hz,1H), 6.84 (s, 1H), 6.95 (s, 1H), 7.11 (s, 1H), 7.44 (d, J=1.77 Hz, 1H).

Step C: Preparation of 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid[4-((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 191)

To a solution of tert-butyl(S)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate(40.0 mg, 115 μmol) in DCM was added2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (28.0 mg, 127 μmol)followed by TEA (32.411, 231 μmol). The reaction was mixed in a rotaryshaker at 25° C. for 1 hour then quenched with MeOH (100 μl). Aftermixing for 20 minutes TFA (400 μl) was added and the resulting mixturewas heated to 40° C. and mixed for 1 hour. The organic solvent wasremoved under vacuum; the crude residue was dissolved in acetonitrile(0.5 mL), neutralized with saturated bicarbonate and subjected topurification by preparative LCMS. The proper fractions were pooled,frozen and lyophilized to afford the title compound as an off whitesolid (16.7% yield). LCMS m/z=431.3 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δppm 1.16 (d, J=6.82 Hz, 3H), 3.48-3.58 (m, 1H), 3.71 (s, 3H), 3.99-4.08(m, 2H), 6.36 (d, J=1.77 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H), 7.50 (d,J=1.77 Hz, 1H), 7.60 (d, J=8.59 Hz, 1H), 7.71 (d, J=2.53 Hz, 2H),7.82-7.91 (m, 2H), 10.35 (s, 1H).

Example 6.2 Preparation of 2,2-Difluoro-benzo[1,3]dioxole-4-carboxylicacid [4-((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 25)

The title compound was prepared in a similar manner as described inExample 6.1, Step C to yield an oily residue in 23.1% yield. LCMSm/z=431.3 (M+H),

Example 6.3 Preparation of 2,5-Dichloro-thiophene-3-carboxylic acid[4-((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 307)

The title compound was prepared in a similar manner as described inExample 6.1, Step C to yield an oily residue in 28.5% yield. LCMS m/z425.2 (M+H), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.82 Hz, 3H),3.48-3.58 (m, 1H), 3.71 (s, 3H), 3.99-4.08 (m, 2H), 6.35 (d, J=2.02 Hz,1H), 7.23 (d, J=9.09 Hz, 1H), 7.47-7.52 (m, 2H), 7.64 (d, J=2.53 Hz,1H), 7.78 (dd, J=9.09, 2.53 Hz, 1H), 7.90-8.09 (bs, 2H), 10.35 (s, 1H).

Example 6.4 Preparation ofN-[4(S)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide(Compound 295)

The title compound was prepared in a similar manner as described inExample 6.1, Step C to yield an oily residue in 31.9% yield. LCMSm/z=435.4 (M+H), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.82 Hz,3H), 3.48-3.58 (m, 1H), 3.71 (s, 3H), 3.99-4.08 (m, 2H), 6.37 (d, J=1.77Hz, 1H), 7.24 (d, J=9.09 Hz, 1H), 7.48-7.51 (m, 1H), 7.54 (d, J=8.59 Hz,2H), 7.73 (d, J=2.27 Hz, 1H), 7.86 (dd, J=8.84, 2.53 Hz, 1H), 7.90-8.06(bs, 2H), 8.08 (d, J=8.84 Hz, 2H), 10.43 (s, 1H).

Example 6.5 Preparation ofN-[4(S)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 286)

The title compound was prepared in a similar manner as described inExample 6.1, Step C to yield an oily residue in 31.4% yield. LCMSm/z=381.4 (M+H), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.57 Hz,3H), 3.48-3.58 (m, 1H), 3.71 (s, 3H), 3.84 (s, 3H), 3.99-4.08 (m, 2H),6.37 (d, J=2.02 Hz, 1H), 7.16 (dd, J=8.21, 2.40 Hz, 1H), 7.24 (d, J=9.09Hz, 1H), 7.42-7.46 (m, 1H), 7.46-7.51 (m, 2H), 7.52-7.56 (m, 1H), 7.73(d, J=2.53 Hz, 1H), 7.87 (dd, J=8.84, 2.53 Hz, 1H), 7.90-8.06 (bs, 2H),10.29 (s, 1H).

Example 6.6 Preparation ofN-[4(S)-2-Amino-3-methyl-butoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 72)

The title compound was prepared in a similar manner as described inExample 6.1, Step C to yield an oily residue in 13.99% yield. LCMSm/z=409.4 (M+H).

Example 6.7 Preparation of 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 138) Step A: Preparation of the intermediateN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide

To a solution of 5-methylisoxazole-3-carboxylic acid (284.0 mg, 2236.0μmol) dissolved in DCM (10.0 mL) was added HATU (1020.0 mg, 2683.0 μmol)followed by DIEA (586 μl, 3353 μmol). The solution was stirred at roomtemperature for 5 minutes. 4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol(500.00 mg, 2236 μmol) was added and the reaction mixture was stirred at25° C. for 15 hours. The reaction mixture was subjected to purificationby column chromatography (ethyl acetate:hexane 50:50) to afford thetitle compound as an off-white solid in 59.0% yield. LCMS m/z=333.2(M+H), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.69 (s, 3H), 3.66 (s, 3H), 6.64(s, 1H), 7.00 (d, J=8.84 Hz, 1H), 7.61 (s, 1H), 7.64 (d, J=2.53 Hz, 1H),7.73 (dd, J=8.84, 2.53 Hz, 1H), 10.04 (s, 1H), 10.60 (s, 1H).

Step B: 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 138)

Weighed polymer supported Triphenylphosphine (181 mg, 271 μmol, 3 eq;1.5 mmol/gm) into a 20 mL scintillation vial; capped and flushed withnitrogen. The resin was then suspended in 2.0 mL dry THF and mixed in arotary shaker for 2 minutes.N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide(30.00 mg, 90.20 μmol) was added. The suspension was mixed briefly thenDIAD (diisopropyl azodicarboxylate, 27.94 μl, 144.3 μmol) was added.After 30 minutes in a rotary shaker a solution of (S)-tert-butyl1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) in 0.5 mL of dryTHF was added. The resulting suspension was heated to 65° C. and mixedovernight. LCMS showed that the reaction did not go to completion. Afresh batch of DIAD (27.94 μl, 144.3 μmol) and (S)-tert-butyl1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) were added to thereaction mixture and the suspension was heated to 65° C. and mixedovernight. The suspension was filtered and the resin washed with THF(3×3 mL). The filtrate and washings were combined and concentrated undervacuum. The resulting residue was dissolved in 20% TFA in DCM (2.0 mL),heated to 65° C. and mixed in a rotary shaker for 1.0 hour. The organicsolvent was removed under vacuum and the crude residue was dissolved inacetonitrile (0.8 mL), neutralized with saturated NaHCO₃ and subjectedto purification by preparative LCMS. The desired fractions were pooled,frozen and lyophilized to afford the title compound as an off-whitesolid (21.34% yield). LCMS m/z=390.3 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δppm 1.16 (d, J=6.82 Hz, 3H), 2.54 (s, 3H), 3.46-3.57 (m, 1H), 3.66 (bs,3H), 3.95-4.16 (m, 2H), 6.66 (s, 1H), 7.35 (dd, J=9.09, 2.53 Hz, 1H),7.66 (s, 1H), 7.74 (d, J=2.53 Hz, 1H), 7.95 (dd, J=9.09, 2.53 Hz, 1H),7.97-8.04 (bs, 2H), 10.76 (s, 1H).

Example 6.8 5-Methyl-isoxazole-3-carboxylic acid[4-(2-amino-2-(tetrahydro-pyran-4-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 276)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 3.62% yield. LCMSm/z=460.4 (M+H).

Example 6.9 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-3,3-dimethyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 327)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 30.8% yield. LCMSm/z=432.4 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (s, 9H), 2.54 (s,3H), 3.46-3.57 (m, 1H), 3.66 (bs, 3H), 3.95-4.16 (m, 2H), 6.66 (s, 1H),7.35 (dd, J=9.09, 2.53 Hz, 1H), 7.66 (s, 1H), 7.74 (d, J=2.53 Hz, 1H),7.95 (dd, J=9.09, 2.53 Hz, 1H), 7.97-8.02 (bs, 2H), 10.76 (s, 1H).

Example 6.10 5-Methyl-isoxazole-3-carboxylic acid[4-((R)-2-amino-3-methyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 85)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 5.84% yield. LCMSm/z=418.5 (M+H).

Example 6.11 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-3-cyclohexyl-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 70)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 26.32% yield. LCMSm/z=472.6 (M+H).

Example 6.12 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-2-cyclohexyl-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 55)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 25.91% yield. LCMSm/z=458.4 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86-1.75 (m, 11H),2.54 (s, 3H), 3.13-3.21 (bs, 1H), 3.66 (s, 3H), 3.99-4.29 (m, 2H), 6.66(s, 1H), 7.35 (dd, J=9.09, 2.53 Hz, 1H), 7.66 (s, 1H), 7.74 (d, J=2.53Hz, 1H), 7.95 (dd, J=9.09, 2.53 Hz, 1H), 7.97-8.02 (bs, 2H), 10.76 (s,1H).

Example 6.13 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-2-cyclohexyl-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 336)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 30.52% yield. LCMSm/z=458.3 (M+H).

Example 6.14 5-Methyl-isoxazole-3-carboxylic acid[4-((S)-2-amino-4-methyl-pentyloxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 185)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 32.10% yield. LCMSm/z=432.4 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.86 (m, 6H),1.30-1.44 (m, 2H), 1.47-1.65 (m, 1H), 2.54 (s, 3H), 3.33-3.45 (m, 1H),3.66 (bs, 3H), 3.95-4.16 (m, 2H), 6.66 (s, 1H), 7.35 (dd, J=9.09, 2.53Hz, 1H), 7.66 (s, 1H), 7.74 (d, J=2.53 Hz, 1H), 7.95 (dd, J=9.09, 2.53Hz, 1H), 7.97-8.04 (bs, 2H), 10.76 (s, 1H).

Example 6.15 5-Methyl-isoxazole-3-carboxylic acid[4-((R)-2-amino-4-methyl-pentyloxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 161)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 27.99% yield. LCMSm/z=432.4 (M+H).

Example 6.16N-[4-((S)-2-Amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide(Compound 277)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an off-white solid in 14.76% yield. LCMSm/z=433.4 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.82 Hz,3H), 3.46-3.55 (m, 1H), 3.66 (bs, 3H), 3.84 (bs, 3H), 3.91-4.14 (m, 2H),6.57 (s, 1H), 6.91 (dd, J=8.72, 2.40 Hz, 1H), 6.97 (dd, J=12.63, 2.27Hz, 1H), 7.27 (dd, J=9.09, 2.53 Hz, 1H), 7.65-7.68 (m, 2H), 7.90-7.83(m, 1H), 7.89-8.02 (bs, 2H), 10.27 (s, 1H).

Example 6.17N-[4-((R)-2-Amino-3-methyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 285)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 12.9% yield. LCMSm/z=414.3 (M+H).

Example 6.18N-[4-((R)-2-Amino-2-cyclohexyl-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 158)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 18.1% yield. LCMSm/z=454.3 (M+H).

Example 6.19N-[4-((S)-2-Amino-2-cyclohexyl-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 141)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 16.6% yield. LCMSm/z=454.2 (M+H).

Example 6.20N-[4-((S)-2-Amino-3,3-dimethyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 117)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 2.04% yield. LCMSm/z=428.3 (M+H).

Example 6.21N-[4-((R)-2-Amino-4-methyl-pentyloxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 271)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 5.37% yield. LCMSm/z=428.3 (M+H).

Example 6.22N-[4-((S)-2-Amino-4-methyl-pentyloxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 248)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 4.35% yield. LCMSm/z=428.2 (M+H).

Example 6.23N-[4-((S)-2-Amino-3-methyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-nicotinamide(Compound 233)

The title compound was prepared in a similar manner as described inExample 6.7, Step B to afford an oily residue in 11.1% yield. LCMSm/z=414.3 (M+H).

Example 7 Preparation of Compounds Example 7.1 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 322)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(0.5000 g, 1.161 mmol) and ammonia (0.2515 g, 11.62 mmol) in 20 mL ofmethanol were heated to 150° C. for 30 minutes under microwaveirradiation in a heavy walled sealed tube. The reaction mixture wasconcentrated to produce the crude product that was subjected topurification on HPLC. The proper fractions were collected andlyophilized to afford the title compound as a white solid (TFA salt) in53% yield. LCMS m/z (%)=367 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ 10.2(s, 1H), 7.83 (dd, J₁=2.53 and J₂=8.89 Hz, 1H), 7.68 (d, J₁=2.53 Hz,1H), 7.53 (d, J₁=8.08 Hz, 1H), 7.48 (m, 1H), 7.46 (d, J₁=1.78 Hz, 1H),7.43 (d, J₁=8.08 Hz, 1H), 7.19-7.13, (m, 2H), 6.27 (d, J₁=1.77 Hz, 1H),3.95 (t, J₁=5.80 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 2.8 (t, J₁=5.80Hz, 2H).

Example 7.2 Preparation of 6-Chloro-2,3-dihydro-indole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 180) Step A: Preparation of tert-Butyl{2-[2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)phenoxy]ethyl}carbamate

To a mixture of bis(2,5-dioxopyrrolidin-1-yl), carbonate (1.410 g, 5.506mmol) in DMF (50 mL) was added tert-butyl2-(4-amino-2-(4-bromo-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(1.887 g, 4.588 mmol) in DMF (20 mL), at 0° C. dropwise. After addition,the mixture was stirred at room temperature for 2 h. Then it was stirredat 65° C. for 30 min. tert-Butyl{2-[2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-({[(2,5-dioxopyrrolidin-1-yl),oxy]carbonyl}amino), phenoxy]ethyl}carbamate in DMF solution was usedinto next step without further purification. LCMS m/z (%)=552 (M+H ⁷⁹Br,35), 554 (M+H ⁸¹Br, 37)

Step B: Preparation of 6-Chloro-2,3-dihydro-indole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 180)

A mixture of tert-butyl2-(4-amino-2-(4-bromo-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(30 mg, 54 μmol) and 6-chloroindoline (8.3 mg, 54 μmol) in 1 mL of DMFwas stirred at room temperature overnight. Then to the mixture was added1 mL of 2M HCl. The mixture was stirred at room temperature overnight.The mixture was concentrated and the crude product was subjected topurification on HPLC. The proper fractions were collected andlyophilized to afford yellow oil in 20.1% yield. LCMS m/z (%)=492 (M+H³⁵Cl⁷⁹Br, 100). ¹H NMR (400 MHz, MeOD) δ ppm 3.1 (m, 4H), 3.7 (s, 3H),4.1 (m, 3H), 4.2 (m, 1H), 6.8 (dd, J=7.6, 2.0 Hz, 1H), 7.1 (d, J=7.6 Hz,1H), 7.1 (d, J=9.1 Hz, 1H), 7.3 (d, J=3.0 Hz, 1H), 7.5 (s, 1H), 7.6 (dd,J=9.1, 2.5 Hz, 1H), 7.8 (d, J=2.0 Hz, 1H).

Example 7.3 Preparation of 4-Chloro-2,3-dihydro-indole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 81)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 16.5% yield. LCMS m/z (%)=492 (M+H³⁵Cl⁷⁹Br, 100). ¹H NMR (400 MHz, MeOD) δ ppm 3.3 (m, 4H), 3.8 (s, 3H),4.2 (m, 3H), 4.3 (dd, J=11.1, 4.5 Hz, 1H), 7.0 (d, J=8.1 Hz, 1H), 7.2(t, J=8.1 Hz, 1H), 7.3 (m, 1H), 7.4 (d, J=3.0 Hz, 1H), 7.6 (s, 1H), 7.7(dd, J=8.8, 2.8 Hz, 1H), 7.8 (d, J=7.6 Hz, 1H).

Example 7.4 Preparation of 5-Chloro-2,3-dihydro-indole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 160)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 17.7% yield. LCMS m/z (%)=492 (M+H³⁵Cl⁷⁹Br). ¹H NMR (400 MHz, MeOD) δ ppm 3.3 (m, 4H), 3.8 (s, 3H), 4.2(m, 3H), 4.3 (m, 1H), 7.1 (dd, J=8.6, 2.0 Hz, 1H), 7.2 (d, J=2.5 Hz,1H), 7.2 (d, J=9.1 Hz, 1H), 7.4 (d, J=2.5 Hz, 1H), 7.6 (s, 1H), 7.7 (m,1H), 7.9 (d, J=8.6 Hz, 1H).

Example 7.5 Preparation of 3,4-Dihydro-2H-quinoline-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 250)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid. LCMS m/z (%)=471 (M+H).

Example 7.6 Preparation of (S)-2-Methoxymethyl-pyrrolidine-1-carboxylicacid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 149)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 8.51% yield. LCMS m/z (%)=452 (M+).

Example 7.7 Preparation of 5-Bromo-2,3-dihydro-indole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 173)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 5.5% yield. LCMS m/z (%)=536 (M+H⁷⁹Br, 100), 538 (M+H ⁸¹Br, 98). ¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.3 (m,4H), 3.8 (s, 3H), 4.2 (t, J=8.8 Hz, 2H), 4.2 (m, 1H), 4.3 (m, 1H), 7.2(d, J=8.6 Hz, 1H), 7.3 (dd, J=8.6, 2.0 Hz, 1H), 7.4 (m, 1H), 7.4 (d,J=3.0 Hz, 1H), 7.6 (s, 1H), 7.7 (dd, J=8.8, 2.8 Hz, 1H), 7.8 (d, J=8.6Hz, 1H).

Example 7.8 Preparation of Octahydro-quinoline-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 27)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 18.1% yield. LCMS m/z (%)=476 (M+,98). ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.4 (m, 8H), 1.7 (m, 2H), 1.8 (m,2H), 1.9 (m, J=14.4, 4.3 Hz, 3H), 3.3 (t, J=5.6 Hz, 2H), 3.7 (s, 3H),3.9 (d, J=11.1 Hz, 1H), 4.2 (m, 1H), 4.3 (m, 1H), 7.2 (d, J=9.1 Hz, 1H),7.3 (dd, J=2.5, 1.0 Hz, 1H), 7.5 (m, 1H), 7.6 (s, 1H).

Example 7.9 Preparation of Octahydro-isoquinoline-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 41)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 21.0% yield. LCMS m/z (%)=476 (M+,98). ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.5 (m, 7H), 1.7 (m, J=4.5 Hz, 2H),1.9 (m, 3H), 3.2 (m, 1H), 3.2 (dd, J=12.6, 3.5 Hz, 1H), 3.3 (t, J=5.1Hz, 2H), 3.7 (s, 3H), 3.8 (dd, J=13.1, 4.5 Hz, 1H), 3.9 (m, 1H), 4.2 (m,1H), 4.3 (m, 1H), 7.2 (d, J=8.6 Hz, 1H), 7.3 (d, J=2.5 Hz, 1H), 7.5 (m,1H), 7.6 (s, 1H).

Example 7.10 Preparation of6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 196)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 16.2% yield. LCMS m/z (%)=530 (M+).

Example 7.11 Preparation of 4-Methyl-piperazine-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 298)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 61.5% yield. LCMS m/z (%)=437 (M+)

Example 7.12 Preparation ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(Compound 181)

A mixture ofN-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(0.5000 g, 1.195 mmol) and ammonia (0.34 g, 20.0 mmol) in 10 mL ofmethanol were heated to 150° C. for 30 minutes under microwaveirradiation in a heavy walled sealed tube. The reaction mixture wasconcentrated to produce the crude product that was subjected topurification on HPLC. The proper fractions were collected andlyophilized to afford the title compound as a white TFA solid in 53%yield. LCMS m/z (%)=355 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ 10.3 (s,1H), 7.85-7.73 (m, 2H), 7.68 (d, J₁=2.78 Hz, 1H), 7.62-7.53 (m, 1H),7.46 (d, J₁=1.78 Hz, 1H), 7.45-7.42 (m, 2H), 7.18 (d, J₁=8.08 Hz, 1H),6.28 (d, J, =2.01 Hz, 1H), 3.95 (t, J₁=6.06 Hz, 2H), 3.69 (s, 3H), 2.79(t, J₁=6.06 Hz, 2H).

Example 7.13 Preparation of4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 99)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 25.3% yield. LCMS m/z (%)=568 (M+,27). ¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.3 (t, J=5.6 Hz, 2H), 3.7 (dd,J=6.8, 3.3 Hz, 4H), 3.8 (s, 3H), 3.8 (dd, J=6.1, 3.0 Hz, 4H), 4.2 (m,1H), 4.3 (m, 1H), 7.0 (d, J=9.6 Hz, 1H), 7.2 (d, J=8.6 Hz, 1H), 7.3 (d,J=2.5 Hz, 1H), 7.6 (m, 2H), 7.8 (dd, J=9.1, 2.5 Hz, 1H), 8.4 (s, 1H).

Example 7.14 Preparation of4-(3,5-Dichloro-pyridin-4-yl)-piperazine-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 123)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 33.4% yield. LCMS m/z (%)=570(M+H). ¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.3 (t, J=5.6 Hz, 2H), 3.5 (m,4H), 3.7 (m, 4H), 3.8 (s, 3H), 4.2 (dt, J=10.6, 5.6, 4.5 Hz, 1H), 4.3(dt, J=11.0, 5.4, 5.3 Hz, 1H), 7.2 (d, J=9.1 Hz, 1H), 7.3 (d, J=2.5 Hz,1H), 7.6 (m, 2H), 8.4 (s, 2H)

Example 7.15 Preparation of 4-Pyridin-2-yl-piperazine-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 44)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 22.2% yield. LCMS m/z (%)=500 (M+).

Example 7.16 Preparation of 4-(2-Methoxy-phenyl)-piperazine-1-carboxylicacid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 147)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 42.9% yield. LCMS m/z (%)=529 (M+).

Example 7.17 Preparation of 4-(4-Methoxy-phenyl)-piperazine-1-carboxylicacid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 153)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 11.3% yield. LCMS m/z (%)=529 (M+).

Example 7.18 Preparation of 2,5-Dihydro-pyrrole-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 164)

The title compound was prepared in a similar manner as described inExample 7.2 to give a white solid in 43.7% yield. LCMS m/z (%)=406 (M+,100).

Example 7.19 Preparation of 5,6-Dihydro-4H-pyrimidine-1-carboxylic acid[4-(2-amino-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 329)

The title compound was prepared in a similar manner as described inExample 7.2 to give a yellow oil in 27% yield. LCMS m/z (%)=421 (M+).

Example 7.20 Preparation of Acetic acid1-{2-[-(3-methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethylcarbamoyloxy}-ethylester (Compound 345)

To a mixture ofN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(55 mg, 150.1 μmol) and 1-chloroethyl carbonochloridate (17.99 μl, 165.1μmol) in dichloromethane was added Proton-Sponge (35.38 mg, 165.1 μmol)in dichloromethane dropwise at 0° C. The mixture was stirred at 0° C.for 2 hours, and then it was stirred at room temperature overnight. Thesolvent was removed and 4 mL acetic acid was added. To the mixture wasadded mercury acetate (47.33 mg, 165.1 μmol). The mixture was stirred atroom temperature overnight. The solvent was removed and the crudeproduct was purified by flash column chromatography (0-50%EtOAc/n-hexane/silica). The product was obtained as white solid in 43%yield. LCMS m/z (%)=497 (M+H, 100). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.5(d, J=5.6 Hz, 3H), 2.1 (s, 3H), 2.1 (m, J=5.6 Hz, 1H), 3.5 (m, 2H), 3.8(s, 3H), 3.9 (s, 3H), 4.1 (t, J=5.1 Hz, 2H), 4.9 (t, J=6.1 Hz, 1H), 6.3(d, J=2.0 Hz, 1H), 6.8 (q, J=5.6 Hz, 1H), 7.0 (d, J=9.1 Hz, 1H), 7.1 (m,1H), 7.4 (m, 2H), 7.4 (m, 1H), 7.5 (d, J=2.0 Hz, 1H), 7.6 (d, J=2.5 Hz,1H), 7.7 (dd, J=8.8, 2.8 Hz, 1H), 7.8 (s, 1H).

Example 7.21 Preparation ofN-[4-(2-Hexanoylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 346)

To a mixture ofN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.020 g, 0.15 mmol) and triethylamine (0.038 mL, 0.27 mmol) indichloromethane was added hexanoyl chloride (50 mg, 0.14 mmol), dropwiseat room temperature. The mixture was stirred at room temperatureovernight. The reaction was quenched with water, extracted withdichloromethane (3×20 mL) and dried over anhydrous MgSO₄. The crudeproduct was purified by flash column chromatography.(EtOAc/Hexane=50-90%).N-[4-(2-Hexanoylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamidewas obtained as white solid in 43% yield. LCMS m/z (%)=465 (M+H, 100).¹H NMR (400 MHz, CDCl₃) δ ppm 0.9 (t, J=7.1 Hz, 3H), 1.3 (m, 4H), 1.6(m, 2H), 2.1 (m, 2H), 3.5 (q, J=5.4 Hz, 2H), 3.8 (s, 3H), 3.9 (s, 3H),4.0 (t, J=5.1 Hz, 2H), 5.5 (m, 1H), 6.3 (d, J=2.0 Hz, 1H), 7.0 (d, J=9.1Hz, 1H), 7.1 (m, 1H), 7.4 (m, 2H), 7.4 (d, J=2.0 Hz, 1H), 7.6 (d, J=2.0Hz, 1H), 7.6 (d, J=3.0 Hz, 1H), 7.7 (dd, J=8.8, 2.8 Hz, 1H), 7.8 (s,1H).

Example 7.22 Preparation of{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid benzyl ester (Compound 347)

To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl),phenyl)-3-methoxybenzamide (50 mg, 136 μmol) and triethylamine (0.038mL, 0.27 mmol) in dichloromethane was added benzyl chloroformate (26 mg,150 μmol), dropwise at room temperature. The mixture was stirred at roomtemperature overnight. The reaction was quenched with water, extractedwith dichloromethane (3×20 mL) and dried over anhydrous MgSO₄. Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by flash columnchromatography. (EtOAc/Hexane=50-90%).{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl1-carbamic acid benzyl ester was obtained as white solid in 37% yield.LCMS m/z (%)=501 (M+H, 100). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.5 (q, J=5.4Hz, 2H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (t, J=5.1 Hz, 2H), 4.9 (t, J=5.8Hz, 1H), 5.1 (s, 2H), 6.3 (d, J=2.0 Hz, 1H), 7.0 (d, J=8.6 Hz, 1H), 7.1(m, 1H), 7.3 (m, 5H), 7.4 (m, 1H), 7.5 (m, 2H), 7.7 (dd, J=8.8, 2.8 Hz,1H), 7.8 (s, 1H).

Example 7.23 Preparation of{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamicacid 2-chloro-ethyl ester (Compound 341)

To a solution ofN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.5000 g, 1.365 mmol) and N,N-Diisopropylethylamine (0.2383 mL, 1.365mmol) in 1 mL of was added dropwise, 2-Chloroethyl chloroformate (0.1951g, 1.365 mmol). The reaction mixture was stirred overnight at ambienttemperature. Ethanol was removed under vacuum and the crude was purifiedby preparative LCMS (m/z=472). The proper fractions were collected andlyophilized to afford the title compound as an off-white solid in 38%yield. LCMS m/z (%)=472 (M+H ³⁵Cl, 100), 474 (M+H ³⁷Cl, 40). ¹H NMR (400MHz, CDCl₃) δ 8.16 (s, 1H), 7.71 (d, J=2.16 Hz, 1H), 7.68 (d, J=2.01 Hz,1H), 7.45-7.34 (m, 3H), 7.08 (d, J=8.08 Hz, 1H), 6.98 (d, J=8.08 Hz,1H), 6.31 (bs, 1H), 7.19-7.13, (m, 2H), 5.18 (bt, J=5.80 Hz, 1H), 4.28(t, J=6.01 Hz, 2H), 4.03 (t, J=4.80 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H),3.65 (t, J₁=5.80 Hz, 2H), 3.45 (q, J=11.10 Hz, 2H).

Example 7.24 Preparation of Cyclopropanecarboxylic acid[4-(2-amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 328)

A mixture of cyclopropanecarboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-amide (0.500 g,1.714 mmol), Triphenylphosphine (1.438 g, 5.484 mmol) and ethanolamine(0.3308 g, 5.416 mmol) were taken up in 20 mL of anhydrous THF in around bottomed flask. To this was added slowly diisopropylazodicarboxylate (1.08 mL, 5.484 mmol) and stirred at ambienttemperature for 18 hours. The reaction mixture was partitioned betweenaqueous 1N HCl and dichloromethane. The aqueous layer was furtherextracted with dichloromethane (2×). The aqueous solution wasneutralized with 10% NaOH to a pH of 8.0 and extracted with ethylacetate (2×, 50 mL). The ethyl acetate layer was separated, dried overNa₂SO₄ and concentrated to produce the crude product as a hygroscopicsolid, that was subjected to purification on HPLC. The proper fractionswere collected and lyophilized to afford the title compound as a whitesolid in 19% yield (TFA salt). LCMS m/z (%)=335 (M+H ³⁵Cl, 100), 337(M+H ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 10.3 (s, 1H), 7.70 (dd,J₁=2.5 and J₂=9.01 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J₁=2.53 Hz, 1H), 7.21(d, J₁=9.09 Hz, 1H), 4.11-4.22 (m, 2H), 3.64 (s, 3H), 3.10-3.18 (m, 2H),1.78-1.70 (m, 1H), 0.8-0.76 (d, J₁=6.41 Hz, 4H).

Example 8 Preparation of Compounds Example 8.1 Preparation ofN-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide

Cesium carbonate (7.04 g, 21.6 mmol) was added to a solution of2-methyl-2-nitropropyl methanesulfonate (2.39 g, 12.1 mmol) andN-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (2.00 g, 8.65mmol) in dimethylacetamide (15 mL) and the mixture was stirred at 160°C. After 2 h, the solvent was evaporated, and the residue was trituratedwith water. The precipitate was isolated by filtration, washed withwater and dried in vacuo to afford the product (2.38 g, 83%) as a tansolid. LCMS m/z (%)=333.4 (M+H 100%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.47 (s, 6H), 2.02 (s, 3H), 3.53 (s, 3H), 4.32 (s, 2H), 6.15 (d, J=2.02Hz, 1H), 7.14 (d, J=8.84 Hz, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.49 (d,J=2.78 Hz, 1H), 7.62 (dd, J=8.97, 2.65 Hz, 1H), 9.94 (s, 1H).

Example 8.2 Preparation of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline

N-Bromosuccinimide (0.931 g, 5.23 mmol) was added to a supension ofN-(3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide(1.58 g, 4.75 mmol) in 10 mL of methanol, and the mixture was stirred atroom temperature. A clear solution was obtained within minutes. After 20min, a solution of sodium hydroxide (1.14 g, 28.5 mmol) in water (1.00mL, 55.5 mmol) was added, and the solution was heated to 160° C. for 0.5hr under microwave irradiation in a heavy walled sealed tube. Thesolvent was evaporated under reduced pressure, and the residue was takenup in saturated sodium bicarbonate and extracted twice withdichloromethane. The extracts were combined, dried with sodium sulfate,filtered, and evaporated to dryness. The crude product was purified byflash chromatography (ethyl acetate-hexanes 1:2, then 1:1) to afford thetitle compound as an off-white solid (1.07 g, 61%). LCMS m/z (%)=371.0(M+H ⁸¹Br 36%), 369.1 (M+H ⁷⁹Br 30%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.44(s, 3H), 1.50 (s, 3H), 3.63 (s, 3H), 3.81 (d, J=9.85 Hz, 1H), 4.34 (d,J=9.85 Hz, 1H), 6.72 (d, J=1.52 Hz, 1H), 6.87-6.93 (m, 2H), 7.51 (s,1H).

Example 8.3 Preparation ofN-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)-2,2,2-trifluoroacetamide

Trifluoroacetic anhydride (0.35 mL, 2.49 mmol) was added to a solutionof3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline(836 mg, 2.26 mmol) and N,N-diisopropylethylamine (0.44 mL, 2.49 mmol)in dichloromethane, and the solution was stirred at room temperature.After 4 h, the solution was diluted with dichloromethane (30 mL) washedwith water and dried with sodium sulfate. Flash chromatography (ethylacetate-hexanes 1:2) affordedN-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)-2,2,2-trifluoroacetamideas a pale yellow foam (889 mg, 1.91 mmol, 85%). LCMS m/z (%)=467.4 (M+H⁸¹Br 26.3%), 465.2 (M+H ⁷⁹Br 31.5%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49(s, 3H), 1.56 (s, 3H), 3.62 (s, 3H), 4.00 (d, J=9.85 Hz, 1H), 4.50 (d,J=9.60 Hz, 1H), 7.07 (d, J=9.09 Hz, 1H), 7.41 (d, J=2.78 Hz, 1H), 7.53(s, 1H), 7.78 (dd, J=9.09, 2.78 Hz, 1H), 7.95 (s, 1H), (100.0%).

Example 8.4 Preparation ofN-(4-(2-amino-2-methylpropoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl)-2,2,2-trifluoroacetamide

Acetylchloride (1.36 mL, 19.1 mmol) was added slowly to a well-stirredsolution ofN-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)-2,2,2-trifluoroacetamide(889 mg, 1.91 mmol) in methanol (10 mL). Zinc dust (1.25 g, 19.1 mmol)was added in small portions, and the mixture was stirred at 55° C. After2 h, the solvent was removed under reduced pressure, and residue wassuspended in 1M HCl (10 mL) and covered with ethyl acetate. The mixturewas cooled on an ice bath, and ammonium hydroxide was added until allprecipitate dissolved. The layers were separated, and the aqueous layerwas extracted with ethyl acetate. The combined ethyl acetate extractswere washed with brine, dried with sodium sulfate, filtered andevaporated to dryness to yieldN-(4-(2-amino-2-methylpropoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl)-2,2,2-trifluoroacetamideas a white powder (693 mg, 1.59 mmol, 83%). LCMS m/z (%)=437.3 (M+H ⁸¹Br9.0%), 435.2 (M+H ⁷⁹Br 14.0%).

Example 8.5 Preparation oftert-butyl-1-(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenoxy)-2-methylpropan-2-ylcarbamate

Boc-anhydride (459 mg, 2.10 mmol) was added to a mixture ofN-(4-(2-amino-2-methylpropoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl)-2,2,2-trifluoroacetamide(693 mg, 1.59 mmol) and dichloromethane (10 mL) and the reaction wasstirred at room temperature. After three days, the solution was dilutedwith dichloromethane (30 mL) washed with 1M citric acid and water, driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was suspended in methanol (10 mL) and a solution of sodiumhydroxide (200 mg) in water (0.4 mL) was added, and the mixture wasrefluxed for 19 h. The solvent was removed under reduced pressure, andthe residue was partitioned between ethyl acetate and saturated sodiumbicarbonate. The ethyl acetate layer was washed with brine and driedwith sodium sulfate. Flash chromatography (ethyl acetate-hexanes 1:2)affordedtert-butyl-1-(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenoxy)-2-methylpropan-2-ylcarbamateas pale yellow foam (525 mg, 1.22 mmol, 77%). LCMS m/z (%)=537.2 (M+H⁸¹Br 4.9%), 535.2 (M+H ⁷⁹Br 5.7%).

Example 8.6 Preparation of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline

A solution of sodium hydroxide (70 mg, 1.74 mmol) in water (0.15 mL) wasadded to a suspension ofN-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide(84 mg, 0.29 mmol) in methanol (1 mL) and the mixture was stirred at140° C. in a screw capped vial for 90 min. The mixture was allowed tocool to room temperature, and the solvent was removed under reducedpressure. The residue was partitioned between dichloromethane and water,the organic layer was dried with sodium sulfate, filtered and evaporatedto dryness to afford the title compound (62 mg, 0.21 mmol, 74%) as ayellow oil which was used without further purification. LCMS m/z(%)=291.3 (M+H 98%).

Example 8.7 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide(Compound 48)

4-Flurobenzoyl chloride (6.63 μL, 0.056 mmol) was added to a solution oftert-butyl(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenoxy)-2-methylpropan-2-ylcarbamate(0.25 mL of a 0.2M solution in dichloromethane, 0.050 mmol) andN,N-diisopropylethylamine (13.1 μL, 0.075 mmol) in dichloromethane (0.5mL) and the reaction vessel was agitated on a mechanical shakerovernight. TFA (0.25 mL) was added, and the reaction vessel was shakenfor another 30 min. The solvent was evaporated in vacuo, and the crudeproduct was purified by RP-HPLC and lyophilized to give the titlecompound as a TFA-salt (26 mg, 92%). LCMS m/z (%)=463.2 (M+H ⁸¹Br 43%),461.2 (M+H ⁷⁹Br 43%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (s, 3H), 1.11(s, 3H), 3.60 (s, 3H), 3.76 (d, J=9.60 Hz, 1H), 3.92 (d, J=9.85 Hz, 1H),7.21 (d, J=9.09 Hz, 1H), 7.27-7.36 (m, 2H), 7.60 (s, 1H), 7.62 (d,J=2.53 Hz, 1H), 7.86 (s, 3H), 7.87 (dd, J=9.09, 2.53 Hz, 1H), 7.93-8.00(m, 2H), 10.30 (s, 1H).

Example 8.8 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(Compound 40)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (21 mg, 73%). LCMS m/z(%)=463.2 (M+H ⁸¹Br 51%), 461.2 (M+H ⁷⁹Br 50%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.10 (s, 3H), 1.11 (s, 3H), 3.60 (s, 3H), 3.76 (d, J=9.60Hz, 1H), 3.93 (d, J=9.60 Hz, 1H), 7.23 (d, J=9.09 Hz, 1H), 7.35-7.43 (m,1H), 7.50-7.57 (m, 1H), 7.60 (s, 1H), 7.63 (d, J=2.53 Hz, 1H), 7.67-7.72(m, 1H), 7.72-7.77 (m, 1H), 7.87 (s, 3H), 7.88 (dd, J=9.09, 2.53 Hz,1H), 10.35 (s, 1H).

Example 8.9 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-benzamide(Compound 36)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (27 mg, 92%). LCMS m/z(%)=463.2 (M+H ⁸¹Br 45%), 461.2 (M+H ⁷⁹Br 52%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (s, 3H), 1.11 (s, 3H), 3.60 (s, 3H), 3.75 (d, J=9.60Hz, 1H), 3.92 (d, J=9.60 Hz, 1H), 7.22 (d, J=9.09 Hz, 1H), 7.25-7.33 (m,2H), 7.48-7.56 (m, 1H), 7.57-7.64 (m, 3H), 7.83 (dd, J=9.09, 2.78 Hz,1H), 7.84 (s, 3H), 10.47 (s, 1H).

Example 8.10 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-phenyl-acetamide(Compound 34)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (26 mg, 90%). LCMS m/z(%)=459.2 (M+H ⁸¹Br 57%), 457.2 (M+H ⁷⁹Br 45%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.14 (s, 3H), 1.15 (s, 3H), 3.63 (s, 3H), 3.77 (d, J=9.60Hz, 1H), 3.94 (d, J=9.60 Hz, 1H), 7.22 (d, J=9.35 Hz, 1H), 7.22-7.28 (m,1H), 7.29-7.38 (m, 4H), 7.51 (d, J=2.78 Hz, 1H), 7.65 (s, 1H), 7.75 (dd,J=8.97, 2.65 Hz, 1H), 7.90 (s, 3H), 10.29 (s, 1H).

Example 8.11 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 188)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (27 mg, 94%). LCMS m/z(%)=445.2 (M+H ⁸¹Br 41%), 443.2 (M+H ⁷⁹Br 39%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.16 (s, 3H), 1.18 (s, 3H), 3.67 (s, 3H), 3.82 (d, J=9.85Hz, 1H), 3.99 (d, J=9.60 Hz, 1H), 7.28 (d, J=9.09 Hz, 1H), 7.54 (t,J=7.33 Hz, 2H), 7.57-7.64 (m, 1H), 7.67 (s, 1H), 7.71 (d, J=2.53 Hz,1H), 7.84-8.00 (m, 6H), 10.36 (s, 1H).

Example 8.12 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide(Compound 135)

DMF (10 μL) was added to a mixture of 4-trifluoromethylbenzoic acid (61mg, 0.32 mmol) and oxalyl chloride (27 μl, 0.32 mmol) in dichloromethane(0.5 mL) and the mixture was stirred for 45 min at room temperature. Thesolution of the crude acid chloride was added to a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (62 mg,0.21 mmol) and DIEA (146 μl, 0.84 mmol) in dichloromethane (0.5 mL) andthe mixture was stirred at room temperature. After 14 h, the mixture wasdiluted with dichloromethane, washed with 0.5M citric acid and saturatedsodium bicarbonate, dried with sodium sulfate, filtered, and evaporatedto dryness. The residue was suspended in methanol (1 mL) andacetylchloride (164 μl, 2.3 mmol) was added slowly. A clear solution wasobtained. Zinc dust (150 mg, 2.3 mmol) was added, and the mixture wasstirred at 55° C. After 2 h, the mixture was allowed to cool to roomtemperature, and diluted with methanol. The precipitate was removed byfiltration and washed with methanol. The combined washings wereevaporated to dryness. The residue was suspended in 1M HCl, the mixturewas cooled on an ice bath, and made alkaline with ammonium hydroxide.The solution was extracted with ethyl acetate, and the extract waswashed with brine, dried with sodium sulfate, filtered, and evaporatedto dryness. The crude product was purified by RP-HPLC. Thetrifluoroacetate was partitioned between ethyl acetate and saturatedsodium bicarbonate, the organic layer was washed with brine, dried withsodium sulfate, filtered, and evaporated to dryness to afford the freebase (53 mg, 0.12 mmol, 57%). LCMS m/z (%)=433.3 (M+H 60.7%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.95 (s, 6H), 3.67 (s, 2H), 3.68 (s, 3H), 6.28(d, J=1.77 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.48 (d, J=1.77 Hz, 1H),7.70 (d, J=2.53 Hz, 1H), 7.84 (dd, J=8.97, 2.65 Hz, 1H), 7.92 (d, J=8.34Hz, 2H), 8.14 (d, J=8.08 Hz, 2H), 10.46 (s, 1H).

Example 8.13 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-benzamide(Compound 111)

4-Chlorobenzoyl chloride (28 μL, 0.22 mmol) was added to a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (58 mg,0.20 mmol) and N,N-diisopropylethylamine 0.22 mmol) in dichloromethane(0.5 mL) and the mixture was stirred at room temperature. After 1 h, themixture was diluted with dichloromethane, washed with 0.5M citric acidand saturated sodium bicarbonate, dried with sodium sulfate, filtered,and evaporated to dryness. The residue was dissolved in methanol (0.5mL) and acetyl chloride (71 μL, 1.0 mmol) was added slowly whilestirring. Zinc dust (65 mg, 1.0 mmol) was added in small portions, andthe mixture was stirred at 55° C. After 2 h, the mixture was allowed tocool to room temperature, and diluted with methanol. The whiteprecipitate was removed by filtration and washed with methanol. Thecombined washings were evaporated to dryness. The residue was suspendedin 1M HCl, the solution was cooled on an ice bath, and made alkalinewith ammonium hydroxide. The solution was extracted with ethyl acetate,and the extract was washed with brine, dried with sodium sulfate,filtered, and evaporated to dryness. The crude product was purified byRP-HPLC. The trifluoroacetate salt was dissolved in a mixture of ethylacetate and saturated sodium bicarbonate. The organic layer was washedwith brine, dried with sodium sulfate, and evaporated to dryness toafford the free base. The free base was dissolved in mixture of methanoland acetyl chloride (35 μL, 0.5 mmol) and the solution was evaporated todryness to give the title compound as a hydrochloride salt (44 mg, 45%).LCMS m/z (%)=401.3 (M+H ³⁷Cl 13.1%), 399.2 (M+H ³⁵Cl 31.8%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.19 (s, 6H), 3.70 (s, 3H), 3.92 (s, 2H), 6.37 (d,J=1.77 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H), 7.50 (d, J=1.77 Hz, 1H),7.59-7.65 (m, 2H), 7.73 (d, J=2.53 Hz, 1H), 7.87 (dd, J=8.97, 2.65 Hz,1H), 7.95-8.01 (m, 2H), 8.03 (s, 3H), 10.39 (s, 1H).

Example 8.14 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-acetamide(Compound 265)

The title compound was prepared in a similar manner as described inExample 8.13 to give the product (46 mg, 45%). LCMS m/z (%)=415.5 (M+H³⁷Cl 12.3%), 413.4 (M+H ³⁵Cl 39.4%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.17 (s, 6H), 3.64 (s, 2H), 3.66 (s, 3H), 3.87 (s, 2H), 6.32 (d, J=2.02Hz, 1H), 7.19 (d, J=9.09 Hz, 1H), 7.30-7.43 (m, 4H), 7.48 (d, J=1.77 Hz,1H), 7.56 (d, J=2.53 Hz, 1H), 7.66 (dd, J=8.97, 2.65 Hz, 1H), 8.03 (s,3H), 10.34 (s, 1H).

Example 8.15 Preparation ofN-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide

Cesium carbonate (815 mg, 2.50 mmol) was added to a solution ofN-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide(396 mg, 1.00 mmol) and 2-methyl-2-nitropropyl methanesulfonate (276 mg,1.40 mmol) in DMA (2.0 mL) and the mixture was stirred at 160° C. After1 hr, the mixture was allowed to cool to room temperature and pouredinto water, and the resulting suspension was extracted withdichloromethane. The extract was dried with sodium sulfate, filtered,and evaporated to dryness. The crude product was purified by flashchromatography (ethyl acetate-hexanes 1:2) to afford the product (338mg, 68%) as a yellow oil. LCMS m/z (%)=499.5 (M+H ³⁷Cl 31.5%), 497.4(M+H ³⁵Cl 100.0%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.51 (s, 3H), 1.57 (s,3H), 3.64 (s, 3H), 4.01 (d, J=9.85 Hz, 1H), 4.49 (d, J=9.85 Hz, 1H),7.08 (d, J=8.84 Hz, 1H), 7.49 (d, J=2.53 Hz, 1H), 7.51 (s, 1H), 7.65 (t,J=7.71 Hz, 1H), 7.80-7.90 (m, 3H), 8.07 (d, J=7.83 Hz, 1H), 8.13 (s,1H).

Example 8.16 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 228)

Acetyl chloride (97 μl, 1.4 mmol) was added dropwise to a solution ofN-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide(68 mg, 0.136 mmol) in MeOH (2.0 mL). Zinc dust (89 mg, 1.4 mmol) wasadded, and the mixture was stirred at 23° C. After 1 hr, the mixture wasfiltered and the filtrate was evaporated to dryness. The residue wastaken up in ammonium hydroxide (35%), diluted with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried withsodium sulfate, filtered, and evaporated to dryness. The crude productwas dissolved in methanol, a solution of acetyl chloride (15 μl) inmethanol was added, and the solution was evaporated to dryness. Theresidue was dissolved in water-acetonitrile 1:1 and lyophilized toafford the product (57 mg, 83%) as the hydrochloride. LCMS m/z (%)=469.4(M+H ³⁷Cl 58.9%), 467.4 (M+H ³⁵Cl 83.7%). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.19 (s, 3H), 1.20 (s, 3H), 3.66 (s, 3H), 3.87 (d, J=9.60 Hz, 1H),4.02 (d, J=9.85 Hz, 1H), 7.31 (d, J=9.09 Hz, 1H), 7.67 (s, 1H), 7.72 (d,J=2.53 Hz, 1H), 7.80 (t, J=7.71 Hz, 1H), 7.92-8.08 (m, 5H), 8.27 (d,J=8.08 Hz, 1H), 8.30 (s, 1H), 10.58 (s, 1H).

Example 8.17 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-benzamide(Compound 208)

3-Bromobenzoyl chloride (40.0 mg, 182 μmol) was added to a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (44.1mg, 152 μmol) and triethylamine (25.4 μl, 182 μmol) in dichloromethane(500 μl) and the mixture was stirred at room temperature. After 1 h, themixture was diluted with dichloromethane, washed with 1M citric acid,saturated sodium bicarbonate, and water. The extract was dried withsodium sulfate, filtered, and evaporated to dryness. The residue wasdissolved in methyl alcohol (800 μl), acetic acid (200 μl, 3464 μmol)was added, followed by zinc dust (99.3 mg, 1519 μmol) and the mixturewas stirred at room temperature. After 18 h the mixture was madestrongly basic with conc. ammonium hydroxide, and the product wasextracted with ethyl acetate. The ethyl acetate layer was evaporated todryness. The crude product was purified by preparative LCMS andlyophilized to afford the product as a TFA-salt (66 mg, 97%). LCMS m/z(%)=445.6 (M+H ^(Br)81 53.1%), 443.4 (M+H ⁷⁹81 70.0%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.19 (s, 6H), 3.71 (s, 3H), 3.91 (s, 2H), 6.37 (d, J=1.77Hz, 1H), 7.25 (d, J=9.09 Hz, 1H), 7.47-7.54 (m, 2H), 7.71 (d, J=2.53 Hz,1H), 7.78-7.83 (m, 1H), 7.88 (dd, J=8.97, 2.65 Hz, 1H), 7.90-7.99 (m,4H), 8.14 (t, J=1.77 Hz, 1H), 10.40 (s, 1H).

Example 8.18 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethoxy-benzamide(Compound 320)

3-Trifluoromethoxybenzoyl chloride (40.9 mg, 182 μmol) was added to asolution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (44.1mg, 152 μmol) and triethylamine (25.4 μl, 182 μmol) in dichloromethane(500 μl) and the mixture was stirred at room temperature. After 1 h, themixture was diluted with dichloromethane, washed with 1M citric acid,saturated sodium bicarbonate, and water. The extract was dried withsodium sulfate, filtered, and evaporated to dryness. The residue wasdissolved in methyl alcohol (800 μl), acetic acid (200 μl, 3464 μmol)was added, followed by zinc dust (99.3 mg, 1519 μmol) and the mixturewas stirred at room temperature. After 18 h the mixture was madestrongly basic with conc. ammonium hydroxide, and the product wasextracted with ethyl acetate. The ethyl acetate layer was evaporated todryness. The crude product was purified by preparative LCMS to affordthe product as a TFA-salt (59 mg, 87%). LCMS m/z (%)=449.3 (M+H 38.4%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (s, 6H), 3.71 (s, 3H), 3.92 (s,2H), 6.37 (d, J=1.77 Hz, 1H), 7.26 (d, J=9.09 Hz, 1H), 7.51 (d, J=1.77Hz, 1H), 7.59-7.66 (m, 1H), 7.69 (d, J=7.83 Hz, 1H), 7.72 (d, J=2.53 Hz,1H), 7.87 (dd, J=8.97, 2.65 Hz, 1H), 7.91 (s, 1H), 7.95 (s, 3H), 8.01(d, J=8.08 Hz, 1H), 10.45 (s, 1H).

Example 8.19 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 308)

3-Trifluoromethylbenzoyl chloride (38.0 mg, 182 μmol) was added to asolution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (44.1mg, 152 μmol) and triethylamine (25.4 μl, 182 μmol) in dichloromethane(500 μl) and the mixture was stirred at room temperature. After 1 h, themixture was diluted with dichloromethane, washed with 1M citric acid,saturated sodium bicarbonate, and water. The extract was dried withsodium sulfate, filtered, and evaporated to dryness. The residue wasdissolved in methyl alcohol (800 μl), acetic acid (200 μl, 3464 μmol)was added, followed by zinc dust (99.3 mg, 1519 μmol) and the mixturewas stirred at room temperature. After 18 h the mixture was madestrongly basic with conc. ammonium hydroxide, and the product wasextracted with ethyl acetate. The ethyl acetate layer was evaporated todryness. The crude product was purified by preparative LCMS to affordthe product as a TFA-salt (51 mg, 77%). LCMS m/z (%)=433.3 (M+H 62.1%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (s, 6H), 3.71 (s, 3H), 3.92 (s,2H), 6.37 (d, J=1.77 Hz, 1H), 7.27 (d, J=8.84 Hz, 1H), 7.51 (d, J=1.77Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.80 (t, J=7.83 Hz, 1H), 7.88 (dd,J=8.97, 2.65 Hz, 1H), 7.92 (s, 3H), 7.96-8.01 (m, 1H), 8.27 (s, 1H),8.29 (s, 1H), 10.53 (s, 1H).

Example 8.20 Preparation of4-Acetylamino-N-[4-(2-amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 287)

4-Acetamidobenzoyl chloride (11 mg, 0.06 mmol) was added to a solutionof3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline(18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) indichloromethane (0.5 mL) and the mixture was stirred at roomtemperature. After 1 h, the solution was diluted with dichloromethane,washed with 1M hydrochloric acid and saturated sodium bicarbonate, driedwith sodium sulfate, filtered, and evaporated to dryness. The residuewas dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was addedfollowed by zinc dust (33 mg) and the mixture was stirred at roomtemperature. After 4 h, the suspension was made basic with ammoniumhydroxide and extracted twice with ethyl acetate. The combined extractswere evaporated to dryness, purified by preparative LCMS and lyophilizedto give the product (5.6 mg, 22%) as a TFA-salt. LCMS m/z (%)=502.3 (M+H⁸¹Br 42.9%), 500.4 (M+H ⁷⁹Br 52.1%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.16 (s, 3H), 1.18 (s, 3H), 2.08 (s, 3H), 3.67 (s, 3H), 3.82 (d, J=9.60Hz, 1H), 3.98 (d, J=9.85 Hz, 1H), 7.27 (d, J=9.09 Hz, 1H), 7.67 (s, 1H),7.69 (d, J=2.78 Hz, 1H), 7.71 (d, J=8.84 Hz, 2H), 7.85-7.91 (m, 3H),7.91 (d, J=8.84 Hz, 2H), 7.95 (dd, J=8.97, 2.65 Hz, 1H), 10.22 (s, 1H),10.23 (s, 1H).

Example 8.21 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-benzamide(Compound 281)

3-Bromobenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline(18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) indichloromethane (0.5 mL) and the mixture was stirred at roomtemperature. After 1 h, the solution was diluted with dichloromethane,washed with 1M hydrochloric acid and saturated sodium bicarbonate, driedwith sodium sulfate, filtered, and evaporated to dryness. The residuewas dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was addedfollowed by zinc dust (33 mg) and the mixture was stirred at roomtemperature. After 4 h, the suspension was made basic with ammoniumhydroxide and extracted twice with ethyl acetate. The combined extractswere evaporated to dryness, purified by preparative LCMS and lyophilizedto give the product (24 mg, 91%) as a TFA-salt. LCMS m/z (%)=525.5 (M+H⁸¹Br₂ 34.2%), 523.3 (M+H⁷⁹Br⁸¹Br 100.0%), 521.4 (M+H ⁷⁹Br₂ 12.6%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.16 (s, 3H), 1.18 (s, 3H), 3.67 (s, 3H),3.83 (d, J=9.60 Hz, 1H), 3.99 (d, J=9.60 Hz, 1H), 7.29 (d, J=9.09 Hz,1H), 7.51 (t, J=7.83 Hz, 1H), 7.67 (s, 1H), 7.69 (d, J=2.53 Hz, 1H),7.78-7.84 (m, 1H), 7.84-7.92 (m, 3H), 7.92-7.98 (m, 2H), 8.14 (t, J=1.77Hz, 1H), 10.44 (s, 1H).

Example 8.22 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethoxy-benzamide(Compound 275)

3-Trifluoromethoxybenzoyl chloride (12 mg, 0.06 mmol) was added to asolution of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline(18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) indichloromethane (0.5 mL) and the mixture was stirred at roomtemperature. After 1 h, the solution was diluted with dichloromethane,washed with 1M hydrochloric acid and saturated sodium bicarbonate, driedwith sodium sulfate, filtered, and evaporated to dryness. The residuewas dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was addedfollowed by zinc dust (33 mg) and the mixture was stirred at roomtemperature. After 4 h, the suspension was made basic with ammoniumhydroxide and extracted twice with ethyl acetate. The combined extractswere evaporated to dryness, purified by preparative LCMS and lyophilizedto give the product (21 mg, 81%) as a TFA-salt. LCMS m/z (%)=529.3 (M+H⁸¹Br 76.1%), 527.5 (M+H ⁷⁹Br 64.8%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.17 (s, 3H), 1.18 (s, 3H), 3.67 (s, 3H), 3.84 (d, J=9.85 Hz, 1H), 4.00(d, J=9.85 Hz, 1H), 7.30 (d, J=9.09 Hz, 1H), 7.60-7.65 (m, 1H), 7.67 (s,1H), 7.68-7.73 (m, 2H), 7.85-7.93 (m, 4H), 7.95 (dd, J=8.97, 2.65 Hz,1H), 8.01 (d, J=7.83 Hz, 1H), 10.48 (s, 1H).

Example 8.23 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 89)

A solution of 3-trifluoromethylbenzoyl chloride (17 μl, 0.11 mmol),N,N-diisopropylethylamine (21 μl, 0.12 mmol) and3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline(37 mg, 0.10 mmol) in 0.5 mL of dichloromethane was stirred at roomtemperature. After 1 h the solution was diluted with dichloromethane,washed with 1M hydrochloric acid and saturated sodium bicarbonate, driedwith sodium sulfate, filtered, and evaporated to dryness. The residuewas taken up in methanol (0.4 mL), acetic acid (114 μl, 2.0 mmol) wasadded followed by zinc dust (65 mg, 1.0 mmol) and the mixture wasstirred at room temperature. After 1 h the mixture was made stronglybasic with conc ammonium hydroxide, and the product was extracted withethyl acetate. The ethyl acetate layer was washed with brine, dried withsodium sulfate, filtered, and evaporated to dryness. The crude productwas purified by preparative LCMS and lyophilized to afford the product(46 mg, 74%) as a TFA-salt. LCMS m/z (%)=513.5 (M+H ⁸¹Br 71.7%), 511.3(M+H ⁷⁹Br 82.9%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 3H), 1.18 (s,3H), 3.67 (s, 3H), 3.84 (d, J=9.60 Hz, 1H), 4.00 (d, J=9.85 Hz, 1H),7.31 (d, J=9.09 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=2.78 Hz, 1H), 7.80 (t,J=7.71 Hz, 1H), 7.86-7.94 (m, 3H), 7.94-8.01 (m, 2H), 8.26 (d, J=8.08Hz, 1H), 8.29 (s, 1H), 10.57 (s, 1H).

Example 8.24 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide(Compound 69)

HATU (53.2 mg, 0.140 mmol) was added to a solution of4-trifluoromethyl-benzoic acid (26.6 mg, 0.140 mmol) and triethylamine(0.0279 mL, 0.200 mmol) in dichloromethane (0.4 mL) and the mixture wasstirred at room temperature. After 15 min, a solution of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline(36.9 mg, 0.100 mmol) in dichloromethane (0.4 mL) was added and stirringwas continued at room temperature. After 2 hr, the mixture was dilutedwith dichloromethane, and washed with 1M citric acid, saturated sodiumbicarbonate, and water. The extract was evaporated to dryness, and theresidue was dissolved in methanol (1 mL). Acetic acid (1.00 mL, 17.5mmol) was added followed by zinc dust (65.4 mg, 1.00 mmol) and themixture was stirred at room temperature. After 18 h the mixture was madestrongly basic with conc. ammonium hydroxide, and the product wasextracted with ethyl acetate. The ethyl acetate layer was evaporated todryness. The crude product was purified by preparative LCMS.

The product containing fractions were combined and concentrated in vacuoto one third of the original volume. The solution was made alkaline with5M sodium hydroxide, and the free base was extracted with ethyl acetate.The organic layer was dried with sodium sulfate, filtered, andevaporated to dryness. The residue was dissolved in a solution of acetylchloride (14.8 μl, 207 μmol) in methanol (1 mL), the solution wasevaporated to dryness, and the product was dried in vacuo over KOH. Theresidue was dissolved in 50% acetonitrile and lyophilized to give thehydrochloride salt (27 mg, 49%). LCMS m/z (%)=513.4 (M+H ⁸¹Br 55.6%),511.4 (M+H ⁷⁹Br 66.2%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 3H),1.18 (s, 3H), 3.67 (s, 3H), 3.84 (d, J=9.60 Hz, 1H), 4.01 (d, J=9.60 Hz,1H), 7.30 (d, J=9.35 Hz, 1H), 7.67 (s, 1H), 7.71 (d, J=2.78 Hz, 1H),7.90-8.02 (m, 6H), 8.15 (d, J=8.34 Hz, 2H), 10.58 (s, 1H).

Example 8.25 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-benzamide(Compound 54)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (25 mg, 82%). LCMS m/z(%)=475.3 (M+H ⁸¹Br 64%), 473.4 (M+H ⁷⁹Br 71%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (s, 3H), 1.11 (s, 3H), 3.60 (s, 3H), 3.75 (d, J=9.60Hz, 1H), 3.77 (s, 3H), 3.92 (d, J=9.60 Hz, 1H), 7.00 (d, J=8.59 Hz, 2H),7.20 (d, J=9.09 Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=2.53 Hz, 1H),7.84-7.93 (m, 6H), 10.13 (s, 1H).

Example 8.26 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 335)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (27 mg, 88%). LCMS m/z(%)=475.4 (M+H ⁸¹Br 67%), 473.5 (M+H ⁷⁹Br 72%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.10 (s, 3H), 1.11 (s, 3H), 3.60 (s, 3H), 3.72-3.80 (m,4H), 3.92 (d, J=9.60 Hz, 1H), 7.10 (dd, J=8.34, 2.53 Hz, 1H), 7.22 (d,J=9.09 Hz, 1H), 7.36-7.43 (m, 2H), 7.43-7.50 (m, 1H), 7.60 (s, 1H), 7.64(d, J=2.53 Hz, 1H), 7.86 (s, 3H), 7.88 (dd, J=9.09, 2.53 Hz, 1H), 10.25(s, 1H).

Example 8.27 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-methoxy-benzamide(Compound 323)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (25 mg, 82%). LCMS m/z(%)=475.4 (M+H ⁸¹Br 49%), 473.5 (M+H ⁷⁹Br 78%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (s, 3H), 1.11 (s, 3H), 3.60 (s, 3H), 3.74 (d, J=9.85Hz, 1H), 3.82 (s, 3H), 3.91 (d, J=9.60 Hz, 1H), 7.00 (t, J=7.45 Hz, 1H),7.12 (d, J=8.34 Hz, 1H), 7.19 (d, J=9.09 Hz, 1H), 7.40-7.48 (m, 1H),7.56 (dd, J=7.58, 1.77 Hz, 1H), 7.60 (s, 1H), 7.61 (d, J=2.78 Hz, 1H),7.88 (s, 3H), 7.85 (dd, J=9.09, 2.53 Hz, 1H), 10.14 (s, 1H).

Example 8.28 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-benzamide(Compound 177)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (24 mg, 82%). LCMS m/z(%)=481.4 (M+H ⁸¹Br³⁷Cl 25%), 479.1 (M+H ⁸¹Br³⁷Cl and ⁷⁹Br³⁵Cl 100%),473.5 (M+H⁷⁹Br³⁵Cl 70%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (s, 3H),1.18 (s, 3H), 3.67 (s, 3H), 3.83 (d, J=9.60 Hz, 1H), 3.99 (d, J=9.85 Hz,1H), 7.29 (d, J=9.09 Hz, 1H), 7.60-7.64 (m, 2H), 7.67 (s, 1H), 7.69 (d,J=2.78 Hz, 1H), 7.92 (s, 3H), 7.95 (dd, J=9.09, 2.78 Hz, 1H), 7.97-8.00(m, J=8.59 Hz, 2H), 10.42 (s, 1H).

Example 8.29 Preparation ofN-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-benzamide(Compound 159)

The title compound was prepared in a similar manner as described inExample 8.7 to give the product as a TFA-salt (20 mg, 80%). LCMS m/z(%)=481.1 (M+H ⁸¹Br³⁷Cl 22%), 479.1 (M+H ⁸¹Br³⁷Cl and ⁷⁹Br³⁵Cl 100%),473.5 (M+H⁷⁹Br³⁵Cl 67%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (s, 3H),1.18 (s, 3H), 3.67 (s, 3H), 3.83 (d, J=9.60 Hz, 1H), 4.00 (d, J=9.60 Hz,1H), 7.29 (d, J=9.09 Hz, 1H), 7.58 (t, J=7.96 Hz, 1H), 7.66-7.69 (m,1H), 7.67 (s, 1H), 7.70 (d, J=2.53 Hz, 1H), 7.89-7.93 (m, 1H), 7.95 (dd,J=8.97, 2.65 Hz, 1H), 7.98 (s, 3H), 8.01 (t, J=1.89 Hz, 1H), 10.46 (s,1H).

Example 9 Receptor Expression

A. pCMV

Although a variety of expression vectors are available to those in theart, it is preferred that the vector utilized be pCMV. This vector wasdeposited with the American Type Culture Collection (ATCC) on Oct. 13,1998 (10801 University Blvd., Manassas, Va. 20110-2209 USA) under theprovisions of the Budapest Treaty for the International Recognition ofthe Deposit of Microorganisms for the Purpose of Patent Procedure. TheDNA was tested by the ATCC and determined to be viable. The ATCC hasassigned the following deposit number to pCMV: ATCC #203351.

B. Transfection Procedure

For the IP accumulation assay (Example 10), HEK293 cells weretransfected while for the DOI binding assay (Example 11) COS7 cells weretransfected. Several protocols well known in the art can be used totransfect cells. The following protocol is representative of thetransfection procedures used herein for COS7 or 293 cells.

On day one, COS-7 cells were plated onto 24 well plates, usually 1×10⁵cells/well or 2×10⁵ cells/well, respectively. On day two, the cells weretransfected by first mixing 0.25 μg cDNA in 50 μL serum-free DMEM/welland then 2 μl lipofectamine in 50 μL serum-free DMEM/well. The solutions(“transfection media”) were gently mixed and incubated for 15-30 minutesat room temperature. The cells were washed with 0.5 mL PBS and then 400μL of serum free media was mixed with the transfection media and addedto the cells. The cells were then incubated for 3-4 hours at 37° C./5%CO₂. Then the transfection media was removed and replaced with 1 mL/wellof regular growth media.

For 293 cells, on day one, 13×10⁶ 293 cells per 150 mm plate were platedout. On day two, 2 mL of serum OptimemI (Invitrogen Corporation) wasadded per plate followed by addition of 60 μL of lipofectamine and 16 μgof cDNA. Note that lipofectamine must be added to the OptimemI and mixedwell before addition of cDNA. While complexes between lipofectamine andthe cDNA are forming, media was carefully aspirated and cells weregently rinsed with 5 mL of OptimemI media followed by carefulaspiration. Then 12 mL of OptimemI was added to each plate and 2 mL oftransfection solution was added followed by a 5 hour incubation at 37°C. in a 5% CO₂ incubator. Plates were then carefully aspirated and 25 mLof Complete Media were added to each plate and cells were then incubateduntil used.

Example 10 Inositol Phosphate (IP) Accumulation Assays

A. 5-HT_(2A) Receptor

Compounds of the invention are tested for their ability to activate a5-HT_(2A) receptor clone using an IP accumulation assay. Briefly, HEK293cells are transiently transfected with a pCMV expression vectorcontaining a human 5-HT_(2A) receptor (for the sequence of the receptorsee U.S. Pat. No. 6,541,209, SEQ ID NO:24) as described in Example 9. AnIP accumulation assay is performed as described below.

B. Constitutively Active 5-HT_(2A) Receptor

Compounds of the invention are tested for their ability to inhibit aconstitutively active 5-HT_(2A) receptor clone using an IP accumulationassay. Briefly, 293 cells are transiently transfected with a pCMVexpression vector containing a constitutively active human 5-HT_(2A)receptor (for the sequence of the receptor see U.S. Pat. No. 6,541,209,SEQ ID NO:30) as described in Example 9. The constitutively active human5-HT_(2A) receptor contained the human 5-HT_(2A) receptor described inpart A except that intracellular loop 3 (IC3) and the cytoplamic tailare replaced by the corresponding human INI 5-HT2C cDNA. An IPaccumulation assay is performed as described below.

C. IP Accumulation Assay Protocol

On the day after transfections, media is removed and the cells arewashed with 5 mL PBS followed by careful aspiration. Cells are thentrypsinized with 2 mL of 0.05% trypsin for 20-30 seconds followed byaddition of 10 mL of warmed media, gently titurated to dissociate cells,and an additional 13 mL of warmed media is gently added. Cells are thencounted and 55,000 cells are added to 96-well sterile poly-D-lysinetreated plates. Cells are allowed to attach over a six hour incubationat 37° C. in a 5% CO₂ incubator. Media is then carefully aspirated and100 μL of warm inositol-free media plus 0.5 μCi ³H-inositol is added toeach well and the plates are incubated for 18-20 hours at 37° C. in a 5%CO₂ incubator.

On the next day, media is carefully aspirated and then 0.1 mL of assaymedium is added containing inositol-free/serum free media, 10 μMpargyline, 10 mM lithium chloride, and test compound at indicatedconcentrations. The plates are then incubated for three hours at 37° C.and then wells are carefully aspirated. Then 200 μL of ice-cold 0.1Mformic acid is added to each well. Plates can then be frozen at thispoint at −80° C. until further processed. Frozen plates are then thawedover the course of one hour, and the contents of the wells(approximately 220 μL) are placed over 400 μL of washed ion-exchangeresin (AG 1-X8) contained in a Multi Screen Filtration plate andincubated for 10 minutes followed by filtration under vacuum pressure.Resin is then washed nine times with 200 μL of water and then tritiatedinositol phosphates (IP, IP2, and IP3) are eluted into a collectingplate by the addition of 200 μl of 1M ammonium formate and an additional10 minute incubation. The elutant is then transferred to 20 mLscintillation vials, 8 mL of SuperMix or Hi-Safe scintillation cocktailsis added, and vials are counted for 0.5-1 minutes in a Wallac 1414scintilation counter.

Example 11 Binding Assays

Compounds of the invention were tested for their ability to bind to a5-HT_(2A) receptor clone membrane preparation using a radioligandbinding assay. Briefly, COS cells were transiently transfected with apCMV expression vector containing a human 5-HT_(2A) receptor (for thesequence of the receptor see U.S. Pat. No. 6,541,209, SEQ ID NO:24) asdescribed in Example 9.

A. Preparation of Crude Membrane Preparations for Radioligand BindingAssays

COS7 cells transfected with recombinant human 5-HT_(2A) receptors werecultured for 48 hr post transfection, collected, washed with ice-coldphosphate buffered saline, pH7.4 (PBS), and then centrifuged at 48,000×gfor 20 min at 4° C. The cell pellet was then resuspended in wash buffercontaining 20 mM HEPES pH 7.4 and 0.1 mM EDTA, homogenized on ice usinga Brinkman polytron, and recentrifuged at 48,000×g for 20 min at 4° C.The resultant pellet was then resuspended in 20 mM HEPES, pH 7.4,homogenized on ice, and centrifuged (48,000×g for 20 min at 4° C.).Crude membrane pellets were stored at −80° C. until used for radioligandbinding assays.

B. [¹²⁵I]DOI Radioligand Binding Assay

Radioligand binding assays for human 5-HT_(2A) receptor was conductedusing the 5-HT₂ agonist [¹²⁵I]DOI as radioligand. To define nonspecificbinding, 10 μM DOI was used for all assays. For competitive bindingstudies, 0.5 nM [¹²⁵I]DOI was used and compounds were assayed over arange of 0.01 nM to 10 μM. Assays were conducted in a total volume of200 μl in 96-well Perkin Elmer GF/C filter plates in assay buffer (50 mMTris-HCl, pH 7.4, 0.5 mM EDTA, 5 mM MgCl₂, and 10 μM pargyline). Assayincubations were performed for 60 min at room temperature and wereterminated by rapid filtration under vacuum pressure of the reactionmixture over Whatman GF/C glass fiber filters presoaked in 0.5% PEIusing a Brandell cell harvestor. Filters were then washing several timeswith ice-cold wash buffer (50 mM Tris-HCl, pH 7.4). Plates were thendried at room temperature and counted in a Wallac microBetascintillation counter. Certain compounds of the present invention andtheir corresponding activity values are shown in the following table.

Compound No. IC₅₀ DOI Binding Assay (nM) 32 0.025 303 0.26 197 1.0 771.2 106 91.0Certain other compounds of the invention had activity values rangingfrom about 10 μM to about 0.03 nM in this assay.

Example 12 In Vitro Human Platelet Aggregation Assays

Compounds of the invention were tested for their ability to aggregatehuman platelets. Aggregation assays were performed using a Chrono-LogOptical aggregometer model 410. Human blood (˜100 mL) was collected fromhuman donors into glass Vacutainers containing 3.8% sodium citrate(light blue tops) at room temperature. Platelet rich plasma (PRP) wasisolated via centrifugation at 100 g for 15 min at room temperature.After removal of the aqueous PRP layer, the platelet poor plasma (PPP)was prepared via high speed centrifugation at 2400 g for 20 minPlatelets were counted and their concentration was set to 250,000cells/μl by dilution with PPP. Aggregation assays were conductedaccording to the manufacturer's specifications. Briefly, a suspension of450 μl PRP was stirred in a glass cuvette (1200 rpm) and, after baselinewas established, 1 μM ADP followed by either saline or 1 μM 5HT andcompound of interest (at desired concentrations) were added and theaggregation response recorded. The concentration of ADP used causesapproximately 10-20% of maximal aggregation. The 5-HT concentrationcorresponded to the concentration which produced maximal potentiation.Percent inhibition of aggregation was calculated from the maximumdecrease in optical density of the controls and of the samplescontaining inhibitors. Only the synergistic effect was assessed. Certaincompounds of the invention had activity values ranging from about 10 μMto about 2.0 nM in this assay.

Example 13 Efficacy of Compounds of the Invention in the Attenuation ofDOI-Induced Hypolocomotion in Rats

In this example, compounds of the invention can be tested for inverseagonist activity by determining whether these compounds could attenuateDOI-induced hypolocomotion in rats in a novel environment. DOI is apotent 5-HT_(2A/2C) receptor agonist that crosses the blood-brainbarrier. The standard protocol used is described briefly below.

Animals

Male Sprague-Dawley rats weighing between 200-300 g are used for alltests. Rats are housed three to four per cage. These rats are naïve toexperimental testing and drug treatment. Rats are handled one to threedays before testing to acclimate them to experimental manipulation. Ratsare fasted overnight prior to testing.

Compounds:

(R)-DOI HCl (C₁₁H₁₆INO₂HCl) can be obtained from Sigma-Aldrich, and isdissolved in 0.9% saline. Compounds of the invention are dissolved in100% PEG400. DOI is injected s.c. in a volume of 1 mL/kg, whilecompounds of the invention are administered p.o. in a volume of 2 mL/kg.

Procedure:

The “Motor Monitor” (Hamilton-Kinder, Poway, Calif.) is used for allactivity measurement. This apparatus recorded rears using infraredphotobeams.

Locomotor activity testing is conducted during the light cycle(0630-1830) between 9:00 a.m. and 4:00 p.m. Animals are allowed 30 minacclimation to the testing room before testing began.

In determining the effects of compounds of the invention on DOI-inducedhypoactivity, animals are first injected with vehicle or the compound ofthe invention (50 mmol/kg) in their home cages. Sixty minutes later,saline or DOI (0.3 mg/kg salt) is injected. 10 min after DOIadministration, animals are placed into the activity apparatus andrearing activity is measured for 10 minutes.

Statistics and Results:

Results (total rears over 10 minutes) are analyzed by t-test. P<0.05 isconsidered significant.

Example 14 In Vitro Binding of 5-HT_(2A) Receptor Animals:

Animals (Sprague-Dawley rats) are sacrificed and brains are rapidlydissected and frozen in isopentane maintained at −42° C. Horizontalsections are prepared on a cryostat and maintained at −20° C.

LSD Displacement Protocol:

Lysergic acid diethylamide (LSD) is a potent 5-HT_(2A) receptor anddopamine D₂ receptor ligand. An indication of the selectivity ofcompounds for either or both of these receptors involves displacement ofradiolabeled-bound LSD from pre-treated brain sections. For thesestudies, radiolabeled ¹²⁵I-LSD (NEN Life Sciences, Boston, Mass.,Catalogue number NEX-199) can be utilized; spiperone (RBI, Natick, Mass.Catalogue number s-128) a 5-HT_(2A) receptor and dopamine D₂ receptorantagonist, can also utilized. Buffer consists of 50 nanomolar TRIS-HCl,pH 7.4.

Brain sections are incubated in (a) Buffer plus 1 nanomolar ¹²⁵I-LSD;(b) Buffer plus 1 nanomolar ¹²⁵I-LSD and 1 micromolar spiperone; orBuffer plus 1 nanomolar ¹²⁵I-LSD and 1 micromolar Compound of interestfor 30 minutes at room temperature. Sections are then washed 2×10minutes at 4° C. in Buffer, followed by 20 seconds in distilled H₂O.Slides are then air-dried.

After drying, sections are apposed to x-ray film (Kodak Hyperfilm) andexposed for 4 days.

Example 15 Serotonin 5-HT_(2A) Receptor Occupancy Studies in Monkey

In this example, the 5-HT_(2A) receptor occupancy of a compound of theinvention can be measured. The study can be carried out in rhesusmonkeys using PET and ¹⁸F-altanserin.

Radioligand:

The PET radioligand used for the occupancy studies is ¹⁸F-altanserin.Radiosynthesis of ¹⁸F-altanserin is achieved in high specific activitiesand is suitable for radiolabeling 5-HT_(2A) receptors in vivo (seeStaley et al., Nucl. Med. Biol., 28:271-279 (2001) and references citedwithin). Quality control issues (chemical and radiochemical purity,specific activity, stability etc) and appropriate binding of theradioligand are verified in rat brain slices prior to use in PETexperiments.

Drug Doses and Formulations:

Briefly, the radiopharmaceutical is dissolved in sterile 0.9% saline, pHapprox 6-7. The compounds of the invention are dissolved in 60% PEG400-40% sterile saline on the same day of the PET experiment.

Serotonin 5-HT_(2A) occupancy studies in humans have been reported forM100,907 (Grunder et al., Neuropsychopharmacology, 17:175-185 (1997),and Talvik-Lofti et al., Psychopharmacology, 148:400-403 (2000)). Highoccupancies of the 5-HT_(2A) receptors have been reported for variousoral doses (doses studied ranged from 6 to 20 mg). For example, anoccupancy of >90% was reported for a dose of 20 mg (Talvik-Lofti et al.,supra), which translates to approx. 0.28 mg/kg. It may therefore beanticipated that an i.v. dose of 0.1 to 0.2 mg/kg of M100,907 is likelyto provide high receptor occupancy. A 0.5 mg/kg dose of a Compound ofthe invention can be used in these studies.

PET Experiments:

The monkey is anesthetized by using ketamine (10 mg/kg) and ismaintained using 0.7 to 1.25% isoflurane. Typically, the monkey has twoi.v. lines, one on each arm. One i.v. line is used to administer theradioligand, while the other line is used to draw blood samples forpharmacokinetic data of the radioligand as well as the cold drugs.Generally, rapid blood samples are taken as the radioligand isadministered which then taper out by the end of the scan. A volume ofapproximately 1 mL of blood is taken per time point, which is spun down,and a portion of the plasma is counted for radioactivity in the blood.

An initial control study is carried out in order to measure baselinereceptor densities. PET scans on the monkey are separated by at leasttwo weeks. Unlabeled Compound of the invention is administeredintravenously, dissolved in 80% PEG 400:40% sterile saline.

PET Data Analysis:

PET data are analyzed by using cerebellum as the reference region andusing the distribution volume region (DVR) method. This method has beenapplied for the analysis of ¹⁸F-altanserin PET data in nonhuman primateand human studies (Smith et al., Synapse, 30:380-392 (1998).

Example 16 The Effect of Compounds of the Invention and Zolpidem onDelta Power in Rats

In this example, the effect of Compounds of the invention on sleep andwakefullness can be compared to the reference drug zolpidem. Drugs areadministered during the middle of the light period (inactivity period).

Briefly, Compounds of the invention are tested for their effects onsleep parameters and are compared to zolpidem (5.0 mg/kg, Sigma, St.Louis, Mo.) and vehicle control (80% Tween 80, Sigma, St. Louis, Mo.). Arepeated measures design is employed in which each rat is to receiveseven separate dosings via oral gavage. The first and seventh dosingsare vehicle and the second through sixth are the test compounds andzolpidem given in counter-balanced order. Since all dosings areadministered while the rats are connected to the recording apparatus,60% CO₂/40% O₂ gas is employed for light sedation during the oral gavageprocess. Rats are fully recovered within 60 seconds following theprocedure. A minimum of three days elapses between dosings. In order totest the effect of the compounds on sleep consolidation, dosing occursduring the middle of the rats' normal inactive period (6 hours followinglights on). Dosing typically occurs between 13:15 and 13:45 using a 24hour notation. All dosing solutions are made fresh on the day of dosing.Following each dosing, animals are continuously recorded until lightsout the following day (˜30 hours).

Animal Recording and Surgical Procedures:

Animals are housed in a temperature controlled recording room under a12/12 light/dark cycle (lights on at 7:00 am) and have food and wateravailable ad libitum. Room temperature (24±2° C.), humidity (50±20%relative humidity) and lighting conditions are monitored continuouslyvia computer. Drugs are administered via oral gavage as described above,with a minimum of three days between dosings Animals are inspected dailyin accordance with NIH guidelines.

Eight male Wistar rats (300+25 g; Charles River, Wilmington, Mass.) areprepared with chronic recording implants for continuouselectroencephalograph (EEG) and electromyograph (EMG) recordings. Underisoflurane anesthesia (1-4%), the fur is shaved from the top of theskull and the skin was disinfected with Betadine and alcohol. A dorsalmidline incision is made, the temporalis muscle retracted, and the skullcauterized and thoroughly cleaned with a 2% hydrogen peroxide solution.Stainless steel screws (#000) are implanted into the skull and served asepidural electrodes. EEG electrodes are positioned bilaterally at +2.0mm AP from bregma and 2.0 mm ML and at −6.0 mm AP and 3.0 mm ML.Multi-stranded twisted stainless steel wire electrodes are suturedbilaterally in the neck muscles for recording of the EMG. EMG and EEGelectrodes are soldered to a head plug connector that was affixed to theskull with dental acrylic. Incisions are closed with suture (silk 4-0)and antibiotics administered topically. Pain is relieved by along-lasting analgesic (Buprenorphine) administered intramuscularly oncepost-operatively. Post-surgery, each animal is placed in a clean cageand observed until it is recovered. Animals are permitted a minimum ofone week post-operative recovery before study.

For sleep recordings, animals are connected via a cable and acounter-balanced commutator to a Neurodata model 15 data collectionsystem (Grass-Telefactor, West Warwick, R.I.). The animals are allowedan acclimation period of at least 48 hours before the start of theexperiment and are connected to the recording apparatus continuouslythroughout the experimental period except to replace damaged cables. Theamplified EEG and EMG signals are digitized and stored on a computerusing SleepSign software (Kissei Comtec, Irvine Calif.).

Data Analysis:

EEG and EMG data are scored visually in 10 second epochs for waking (W),REMS, NREMS. Scored data are analyzed and expressed as time spent ineach state per half hour. Sleep bout length and number of bouts for eachstate are calculated in hourly bins. A “bout” consists of a minimum oftwo consecutive epochs of a given state. EEG delta power (0.5-3.5 Hz)within NREMS is also analyzed in hourly bins. The EEG spectra duringNREMS are obtained offline with a fast Fourier transform algorithm onall epochs without artifact. The delta power is normalized to theaverage delta power in NREMS between 23:00 and 1:00, a time when deltapower is normally lowest.

Data are analyzed using repeated measures ANOVA. Light phase and darkphase data are analyzed separately. Both the treatment effect withineach rat and the time by treatment effect within each rat is analyzed.Since two comparisons are made, a minimum value of P<0.025 is requiredfor post hoc analysis. When statistical significance is found from theANOVAs, t-tests are performed comparing all compounds to vehicle and thetest compounds to zolpidem.

Example 17 Efficacy of Compounds of the Invention in the Inhibition ofJC Virus Infection of Human Glial Cells

A compound of the invention can be shown to inhibit JC virus infectionof human glial cells using the in vitro model of Elphick et al. [Science(2004) 306:1380-1383], essentially as described briefly here.

Cells and JC Virus

The human glial cell line SVG (or a suitable subclone thereof, such asSVG-A) is used for these experiments. SVG is a human glial cell lineestablished by transformation of human fetal glial cells by an origindefective SV40 mutant [Major et al., Proc. Natl. Acad. Sci. USA (1985)82:1257-1261]. SVG cells are cultured in Eagle's minimum essentialmedium (Mediatech Inc., Herndon, Va.) supplemented with 10%heat-inactivated fetal bovine serum, and kept in a humidified 37° C. 5%CO₂ incubator.

The Mad-1/SVEΔ strain of JC virus [Vacante et al., Virology (1989)170:353-361] is used for these experiments. While the host range of JCvirus is typically limited to growth in human fetal glial cells, thehost range of Mad-1/SVEΔ extends to human kidney and monkey cell types.Mad-1/SVEΔ is propagated in HEK cells. Virus titer is measured byhemagglutination of human type O erythrocytes.

Assay for Inhibition of JC Virus Infection

SVG cells growing on coverslips are pre-incubated at 37° C. for 45 minwith or without the compound of the invention diluted in mediacontaining 2% FCS. By way of illustration and not limitation, thecompound of the invention is used at a concentration of about 1 nM toabout 100 μM, at a concentration of about 10 nM to about 100 μM, at aconcentration of about 1 nM to about 10 μM, or at a concentration ofabout 10 nM to about 10 μM.

JC virus (Mad-1/SVEΔ) is then added at an MOI of 1.0 and the cells areincubated for 1 hr at 37° C. in the continued presence of the compoundof the invention. The cells are then washed 3× in PBS and fed withgrowth media containing the compound of the invention. At 72 hrpost-infection, V antigen positive cells are scored by indirectimmunofluorescence (see below). Controls include the addition of thecompound of the invention at 24 and 48 h post-infection. The percentageof infected cells in untreated cultures is set at 100%.

Indirect Immunofluorescence

For indirect immunofluorescence analysis of V antigen expression, SVGcells growing on coverslips are fixed in ice cold acetone. To detect Vantigen expression, the cells are then incubated for 30 min at 37° C.with a 1:10 dilution of hybridoma supernatant from PAB597. The PAB597hybridoma produces a monoclonal antibody against the SV40 capsid proteinVP1 which has been shown to cross-react with JC virus VP1. The cells arethen washed and incubated with goat anti-mouse Alexa Fluor 488 secondaryantibody for an additional 30 min After a final wash, the cells arecounterstained with 0.05% Evan's blue, mounted onto glass slides using90% glycerol in PBS and visualized on Nikon E800 epifluorescent scope.Images are captured using a Hamamatsu digital camera and analyzed usingImprovision software.

Example 18 In Vitro Dog Platelet Aggregation Assays

Approximately 50 mL of blood is pooled from 3 male beagles. The protocolfor analyzing the effects of compounds on platelet aggregation areidentical to those used for human platelets (see Example 12, supra)except 5 μM ADP and 2 μM 5-HT were used to stimulate amplification ofplatelet aggregation.

Example 19 Ex-Vivo Dog Whole Blood Aggregation

One hour following PO dosing with a test compound whole blood wascollected from male beagle dogs in a 5 mL vacutainer with exogenousheparin (5 U/mL) added to vacutainer. Aggregation studies were evaluatedby using whole blood Aggregometer (Chronolog Corp.). Briefly, wholeblood (400 uL) was added to saline (600 uL) with constant stirring andactivated with 5 ug of Collagen (Chronolog Corp.). The serotoninresponse was obtained by adding 5-HT (Sigma) to final concentration of2.5 μM. Results: Selected compounds were tested for antiplateletaggregation activity after single bolus oral dosing. The dose thatafforded maximal inhibition of 5-HT amplified platelet aggregation wasidentified and used for comparison.

Example 20 Rat In Vivo Thrombosis, Bleeding, Aggregation, PK AssayThrombosis Formation and Bleeding Time:

This model concomitantly measures thrombus formation, bleeding time,platelet aggregation and drug exposure in a single live dosed rat. Testcompounds are administered to male rats (weighing 250-350 g) via POinjection at varying concentrations depending on compound potencyranging from 1 mpk-100 mpk. Animals are then anesthetized using Nembutalapproximately 30 min post PO. Once the animal is fully anesthetizedusing approved surgical techniques the animal's right femoral artery isisolated in 2 different sections approximately 4-6 mm in length, onearea for probe placement and one for Ferric Chloride patch positioning.The artery is then allowed to stabilize to allow recovery from thesurgery. During stabilization the animal is then intubated and placed ona ventilator (Harvard Apparatus, Inc.) at 75 strokes/min with a volumeof 2.5 cubic cm. Following intubation and after stabilization a microarterial probe (Transonic Systems, Inc) is then placed on the distalisolated femoral artery. Once the probe is in place the flow ismonitored using a Powerlab recording system (AD Instruments) to monitorrate of pulsatile flow. A small piece of filter paper soaked in 30%ferric chloride is placed on the area of the artery upstream of theprobe for 10 min. After 5 min of Ferric Choloride patch placement thelast 3 mm of the rat's tail is removed. The tail is then placed in asaline filled glass vial at 37 degree and the time it took for bleedingto stop is recorded. After the Ferric chloride patch is removed the flowis recorded until the artery is occluded and time to occlusion isrecorded.

Whole Blood Aggregation and PK:

Following measurement of bleeding and time to occlusion 5 mL of blood isobtained for ex-vivo aggregation analysis by cardiac puncture in heparin(5 U/mL). An additional 500 μL of blood is collected in a separatevacutainer for PK analysis (plasma drug concentration). Ex-vivoaggregation studies are evaluated by using whole blood Aggregometer(Chronolog Corp.). Briefly, whole blood (400 μL) is added to saline (600μL) with constant stirring and activated with 2.55 μg of Collagen(Chronolog Corp.). The serotonin response is obtained by adding 5-HT(Sigma) to final concentration of 2.5 μM. Results: Test compounds orreference compounds with acceptable levels of binding to rat 5-HT_(2A)receptors are evaluated for effects of thrombus formation, bleeding andplatelet activity in a single model. This allows for the most accuratedemonstration of separation of the test compound effects on plateletmediated thrombus formation from effects on bleeding.

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but are notlimited to, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1.-52. (canceled)
 53. A method for modulating an activity of a 5-HT_(2A)serotonin receptor by contacting the receptor withN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,comprising administering to an individual in need thereof atherapeutically effective amount of an isolated compound that isN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,or a pharmaceutically acceptable salt thereof.
 54. A method for treatinga 5-HT_(2A) associated disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of an isolated compound that isN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,or a pharmaceutically acceptable salt thereof.
 55. The method accordingto claim 54, wherein said 5-HT_(2A) mediated disorder is a sleepdisorder.
 56. The method according to claim 54, wherein said 5-HT_(2A)mediated disorder is progressive multifocal leukoencephalopathy.
 57. Themethod according to claim 54, wherein said 5-HT_(2A) mediated disorderis hypertension.
 58. The method according to claim 54, wherein said5-HT_(2A) mediated disorder is pain.
 59. The method according to claim54, wherein said 5-HT_(2A) mediated disorder is claudication.
 60. Themethod according to claim 54, wherein said 5-HT_(2A) mediated disorderis peripheral artery disease.
 61. The method according to claim 54,wherein said 5-HT_(2A) mediated disorder is vasoconstriction.
 62. Themethod according to claim 54, wherein said 5-HT_(2A) mediated disorderis vasospasm.
 63. The method according to claim 54, wherein said5-HT_(2A) mediated disorder is thrombosis.
 64. A method for reducingplatelet aggregation in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of anisolated compound that isN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,or a pharmaceutically acceptable salt thereof.
 65. The method of claim64, wherein the individual has coronary artery disease, myocardialinfarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing.
 66. The methodaccording to claim 65, wherein said 5-HT_(2A) mediated disorder isstroke.
 67. A method for reducing risk of blood clot formation in anangioplasty or coronary bypass surgery patient, or a patient sufferingfrom atrial fibrillation, comprising administering to the individual inneed thereof a therapeutically effective amount of an isolated compoundthat isN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,or a pharmaceutically acceptable salt thereof.
 68. A method for treatinga 5-HT_(2A) serotonin receptor associated disorder in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of an isolated compound that isN-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,or a pharmaceutically acceptable salt thereof.